Download Carotid Chemoreceptors and Blood Pressure

Carotid Chemoreceptors and Blood Pressure
Effect of Bilateral Carotid Body Resection on Cardiac
Baroreflex Control of Blood Pressure During Hypoglycemia
Jacqueline K. Limberg, Jennifer L. Taylor, Michael T. Mozer, Simmi Dube, Ananda Basu,
Rita Basu, Robert A. Rizza, Timothy B. Curry, Michael J. Joyner, Erica A. Wehrwein
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
Abstract—Hypoglycemia results in a reduction in cardiac baroreflex sensitivity and a shift in the baroreflex working
range to higher heart rates. This effect is mediated, in part, by the carotid chemoreceptors. Therefore, we hypothesized
hypoglycemia-mediated changes in baroreflex control of heart rate would be blunted in carotid body–resected patients
when compared with healthy controls. Five patients with bilateral carotid body resection for glomus tumors and 10 healthy
controls completed a 180-minute hyperinsulinemic, hypoglycemic (≈3.3 mmol/L) clamp. Changes in heart rate, blood
pressure, and spontaneous cardiac baroreflex sensitivity were assessed. Baseline baroreflex sensitivity was not different
between groups (P>0.05). Hypoglycemia resulted in a reduction in baroreflex sensitivity in both the groups (main effect
of time, P<0.01) and responses were lower in resected patients when compared with controls (main effect of group,
P<0.05). Hypoglycemia resulted in large reductions in systolic (−17±7 mm Hg) and mean (−14±5 mm Hg) blood pressure
in resected patients that were not observed in controls (interaction of group and time, P<0.05). Despite lower blood
pressures, increases in heart rate with hypoglycemia were blunted in resected patients (interaction of group and time,
P<0.01). Major novel findings from this study demonstrate that intact carotid chemoreceptors are essential for increasing
heart rate and maintaining arterial blood pressure during hypoglycemia in humans. These data support a contribution
of the carotid chemoreceptors to blood pressure control and highlight the potential widespread effects of carotid body
resection in humans. (Hypertension. 2015;65:1365-1371. DOI: 10.1161/HYPERTENSIONAHA.115.05325.)
Key Words: blood pressure
■
carotid body tumor
P
eripheral chemoreceptors play a role in reflex responses to
chemical stimuli, including hypoxia, acidosis, and hypoglycemia. The carotid bodies—typically thought of as key
peripheral chemoreceptors—may also have acute and chronic
effects on blood pressure and an inverse relationship between
peripheral chemosensitivity and baroreflex sensitivity has been
shown previously.1–3 For example, transient blockade of peripheral chemoreceptors with hyperoxia temporarily increases
baroreflex sensitivity,2 whereas activation of the peripheral
chemoreceptors with hypoxia decreases baroreflex sensitivity.4
Consistent with the hypoxia data, our laboratory has shown
hypoglycemia results in a reduction in spontaneous cardiac
baroreflex sensitivity (scBRS) in healthy humans.5 In addition,
the chemoreceptors seem to play an important role in resetting
the baroreflex working range during hypoglycemia such that
acute chemoreceptor desensitization results in a blunted rise in
heart rate and reduction in blood pressure.5
Bilateral carotid body resection in humans for removal of
glomus tumors eliminates reflex responses (increases in ventilation and blood pressure) to chemoreceptor stimulation with
hypoxia.6–9 Given the growing interest in carotid body resection
for the treatment of a variety of disorders10 and the potential
■
chemoreceptor cells
■
glucose
widespread physiological effects of such procedures, we
sought to examine cardiac baroreflex sensitivity during hypoglycemia in patients who have undergone bilateral carotid body
resection. We hypothesized that carotid body–resected patients
would exhibit an inability to maintain arterial blood pressure
during hypoglycemia. We further hypothesized changes in
baroreflex control of heart rate during hypoglycemia would
be blunted in carotid body–resected patients compared with
controls. Our hypotheses were based on our previous observations in normal subjects showing hypoglycemia results in a fall
in blood pressure and attenuated heart rate response when the
carotid chemoreceptors are desensitized with hyperoxia.
Methods
Approval
All experiments and procedures were approved by the Institutional
Review Board at Mayo Clinic. Informed consent was obtained in
writing from all subjects before study enrollment and testing. Studies
conformed to the Declaration of Helsinki. Counterregulatory hormone responses to hypoglycemia in control subjects5,11 and carotid
body–resected patients12 and pertinent methods were published
previously.
Received February 9, 2015; first decision February 22, 2015; revision accepted March 23, 2015.
Department of Physiology, Michigan State University, East Lansing (E.A.W.); Departments of Anesthesiology (J.K.L., J.L.T., M.T.M., T.B.C., M.J.J.),
and Endocrinology (S.D., A.B., R.B., R.A.R.), Mayo Clinic, Rochester, MN.
Correspondence to Michael J. Joyner, Department of Anesthesiology, 200 1st St SW, SMH Joseph 4–184, Rochester, MN 55905. E-mail Joyner.
[email protected]
© 2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.115.05325
1365
1366 Hypertension June 2015
Subjects
Table 1. Subject Demographics
All subjects were aged 21 to 55 years, healthy, nonsmokers, nonpregnant/breast feeding, with body mass index 21 to 32 kg/m2. All
carotid body–resected patients received treatment at the Mayo Clinic
in Rochester, MN. Each patient underwent separate surgeries for right
and left removal of carotid body tumors (paraganglioma). During a
screening visit, subjects completed a hypoxic response test to determine carotid body chemosensitivity.12 Subjects were instructed to
avoid exercise, caffeine, medications (except birth control), and alcohol on the day before and day of the study.
Subject
Demographics
Monitoring
A 20-gauge, 5-cm brachial artery catheter was placed under ultrasound guidance after local anesthesia for blood sampling and beatto-beat blood pressure monitoring (TruWave Pressure Transducer;
Edwards Lifesciences, Irvine, CA). Two intravenous catheters were
placed in the arm opposite the brachial arterial catheter for infusions.
Heart rate was monitored with a 5-lead ECG, respirations via a pneumobelt/capnography, and arterial oxygen saturation by a pulse oximeter (Cardiocap/5; Datex-Ohmeda Inc, Louisville, CO).
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
Hyperinsulinemic Hypoglycemic Clamp
Intravenous insulin (Novolin; Novo Nordisk Inc, Princeton, NJ) was
infused at a constant rate of 2.0 mU/kg fat-free mass per minute from
protocol time (T) 0 to T180 minutes and exogenous glucose (50%
dextrose solution [Hospira, Inc, Lake Forest, IL]) was infused in
amounts sufficient to maintain glucose concentrations at hypoglycemic levels (≈3.3 mmol/L).
Protocol
Subjects were admitted to the Clinical Research Unit of the Mayo
Clinic at 17:00 hours on the evening before study. A standard 10
kcal/kg meal (55% carbohydrate, 30% fat, 15% protein) was eaten
between 18:00 and 18:30 hours and the subject fasted thereafter until
the end of the study. In the morning, the brachial artery catheter and
intravenous lines were placed. The insulin infusion was started at
09:00 hours. Arterial blood was drawn every 5 to 10 minutes at the
bedside for measurement of plasma glucose using a glucose oxidase
method (Analox Instruments USA Inc, Lunenberg, MA). Arterial
blood was also drawn at specific time points (T-30, -20, -10, 0, 150,
160, 170, and 180 minutes) for measures of insulin (DxI automated
immunoassay system; Beckman Instruments, Chaska, MN).
Spontaneous Cardiac Baroreflex Sensitivity
Sex, M/F
Control
Patients
7/3
3/2
25±1
40±5*
Height, cm
177±2
175±5
Weight, kg
75±3
80±7
Body fat, %
25±2
27±3
Fat-free mass, kg
56±3
54±5
Glucose, mmol/L
4.6±0.1
4.6±0.1
Total cholesterol, mmol/L
3.8±0.3
4.5±0.4
Triglycerides, mmol/L
0.9±0.1
1.1±0.3
HDL, mmol/L
1.4±0.2
1.5±0.2
LDL, mmol/L
2.0±0.2
2.5±0.3
…
5±2
Age, y
Time from bilateral resection, y
F indicates female; HDL, high-density lipoprotein; LDL, low-density
lipoprotein; and M, male.
*P<0.05 vs control.
using a 2-way, repeated measures ANOVA, to examine the main
effects of group (control and patients), time (baseline, clamp), and
interactions between group and time on main outcome variables. Post
hoc analyses were completed using the Bonferroni test. In all cases,
distributional assumptions were assessed and appropriate transformations or nonparametric analyses (Mann–Whitney rank sum test)
were used if necessary. When appropriate, Pearson product–moment
correlations were used to determine the association between main
outcome variables (eg, scBRS) and descriptive measurements (eg,
hypoxic ventilatory response). All tests were 2-tailed with P≤0.05
considered statistically significant and analysis was completed using
SigmaPlot version 12.0 (Systat Software Inc; San Jose, CA). All values are reported as mean±SE.
Results
Five patients with bilateral carotid body resection and 10
healthy adults participated in this study. Groups were matched
for weight, body composition, and cholesterol levels (Table 1).
scBRS was assessed from 30-minute sections of data during euglycemic baseline (T-30–T0 [baseline]) and steady-state hypoglycaemia
(T150–T180 [clamp]) using methods published previously.5 Briefly,
a computer software program (LabChart7; ADinstruments, Colorado
Springs, CO) selected all sequences of ≥3 successive heart beats, in
which there were concordant increases or decreases in systolic blood
pressure (SBP) and R–R interval. A linear regression was applied to
each of the sequences manually and an average regression slope was
calculated for acceptable sequences (R2>0.80). The operating points for
the relationships were determined as the average heart rate and SBP
from 5-minutes of data collected during selected time points.13 From
the same 5-minute period, we also measured the coefficient of variation
of SBP (% coefficient of variation; (SD/mean)×100)14 and tabulated
the frequency of occurrence of each blood pressure in increments of 2
mm Hg with results presented as frequency distribution curves.15
Data Analysis and Statistics
The number of subjects was determined a priori based on previous
research from resected patients showing n=5 would provide >0.80
power to detect significant differences in baroreflex sensitivity.7
Where relevant, values are reported as an average from T-30 to T0
(baseline) and from T150 to T180 (clamp). Outcome variables were
evaluated as a change from baseline (Δ=clamp−baseline). Subject
characteristics, baseline measures, and change variables (Δ) were
compared using a Student t test. Additional analyses were performed
Figure 1. Reflex responses to hypoxia. The hypoxic ventilatory
response was significantly blunted in resected patients when
compared with controls (*P<0.01 vs control), with no significant
difference in the heart rate response (P=0.24).
Limberg et al Carotid Body Resection and Baroreflex Control 1367
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
Figure 2. Baseline baroreflex sensitivity. Baroreflex sensitivity was not impaired at baseline in resected patients (A, ms/mm Hg, P=0.28; B,
bpm/mm Hg, P=0.48). In addition, blood pressure distribution (% coefficient of variation [CV] of systolic blood pressures) was not different
between groups (C, P=0.11). Columns represent group means. Blood pressure distribution is also shown as a frequency distribution curve
(D and E), which depicts systolic blood pressure±25 mm Hg from average (x axis) and the frequency of occurrence of each level of arterial
pressure in percent of the total time of occurrence (y axis) during 5 minutes.
Carotid body–resected patients were significantly older than
the control group (P<0.01). The hypoxic ventilatory response, a
measure of carotid body chemosensitivity to hypoxia, was significantly blunted in resected patients when compared with controls (P<0.01; Figure 1). There was no difference in the heart
rate response to hypoxia in carotid body–resected patients when
compared with controls (P=0.24; Figure 1). Hypoxic ventilatory response was linearly related to both heart rate response to
hypoxia (r=0.69; P=0.04) and the time from bilateral resection
(r=−0.84; P=0.08). Given the potential for baroreceptor denervation during removal of glomus tumors, it is important to note
scBRS was not impaired at baseline in resected patients (ms/
mm Hg, P=0.28; bpm/mm Hg, P=0.48). In addition, blood pressure distribution (% coefficient of variation of SBPs) was not
different between groups (P=0.11; Figure 2).
As designed, the hyperinsulinemic hypoglycemic clamp
resulted in higher insulin concentrations (baseline to clamp
values: control, 4±1−132±8 μU/mL; patient, 5±2−151±20
μU/mL) and lower glucose concentrations (control,
5.4±0.1−3.4±0.1 mmol/L; patient, 5.4±0.1−3.3±0.1 mmol/L)
in both the groups (main effect of time, P<0.01) as compared
with baseline. The glucose infusion rate required to maintain
steady-state hypoglycemia was not different between control and resected groups (control, 28±4 μmol/kg per minute;
patient, 38±11 μmol/kg per minute; P=0.46). More detailed
discussion of hypoglycemia counterregulation is available in
our previous publications.11,12
Hypoglycemia resulted in a significant reduction in diastolic
blood pressure in both the groups (main effect of time, P<0.01;
Table 2). In control subjects, heart rate increased during hypoglycemia (interaction of group and time, P<0.01) and SBP and
mean blood pressure were maintained at baseline levels (interaction of group and time, P>0.05; Figure 3). By contrast, hypoglycemia resulted in a significant reduction in SBP and mean blood
pressure in carotid body–resected patients (interaction of group
and time, P<0.05; Table 2). Despite lower blood pressures,
increases in heart rate with hypoglycemia were blunted in carotid
body–resected patients when compared with controls (interaction of group and time, P<0.01; Figure 3). Consistent with this
finding, scBRS was reduced from baseline during hypoglycemia
(main effect of time, P<0.01) and was lower in carotid body–
resected patients when compared with controls (main effect of
group, P<0.05; Figure 3). In addition, the change in heart rate
and SBP with hypoglycemia was related to scBRS (HR: ms/
mm Hg, r=0.46, P=0.08; bpm/mm Hg, r=−0.63, P=0.01; SBP:
ms/mm Hg, r=0.61, P=0.02; bpm/mm Hg, r=−0.36, P=0.18).
Despite a reduction in scBRS with hypoglycemia, an increase in
blood pressure distribution (% coefficient of variation of SBPs)
with hypoglycemia was not observed (main effect of time,
P=0.46; interaction of group and time, P=0.52; Figure 4).
Discussion
We demonstrate that intact carotid chemoreceptors are essential for increasing heart rate and maintaining arterial blood
1368 Hypertension June 2015
Table 2. Changes in Hemodynamic Variables During
Hypoglycemia
Hemodynamic
Variables
Carotid Body Resection and Cardiac Baroreflex
Function
Baseline
Clamp
Δ
Control
59±2
75±4*
16±3
Patient
65±4†
72±6
7±2†
Heart rate, bpm
Systolic blood pressure, mm Hg
Control
128±4
131±9
3±6
Patient
135±10
118±8*
−17±7†
Diastolic blood pressure, mm Hg
Control
65±2
57±3*
−8±2
Patient
62±6
50±3*
−12±4
Mean blood pressure, mm Hg
Control
86±3
82±4
−4±2
Patient
87±7
73±4*
−14±5†
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
*Effect of time: P<0.05 vs baseline.
†Effect of group: P<0.05 vs control.
pressure during hypoglycemia in humans. In this context, a
rise in heart rate was not observed in carotid body–resected
patients, despite ≈15 mm Hg reductions in arterial blood pressure during hypoglycemia (Table 2; Figure 3A and 3B). These
observations highlight potential physiological consequences
of carotid body resection in humans.
During surgical removal of carotid body paragangliomas,
branches of the carotid sinus nerves may be damaged and cause
baroreflex failure.16–18 Baroreflex failure (sympathoexcitation,
hypertension, and tachycardia) is often an early postsurgical
response that resolves within months; however, both normalization of blood pressure19 and sustained hypertension19–21 have
been observed in resected patients. Although overt baroreflex
failure occurs in a minority of patients,7,22 baroreflex sensitivity may be ≈50% lower in some patients.7,16,22 In contrast to
previous findings from other cohorts,7,16 we did not observe a
significant impairment in baseline cardiac baroreflex sensitivity in the present group of resected patients.
Despite the relatively small number of patients studied and
the significant age difference between groups, there is clear
overlap in all indices of cardiac baroreflex function and blood
pressure stability between patients and controls (Figure 2A
and 2E). In addition, a post hoc sample size estimate revealed
that 116 subjects would be necessary to provide 80% power
to detect group differences—suggesting any group difference
would be of limited physiological relevance. These findings
support the concept that the carotid body–resected patients
studied had relatively normal baseline cardiac baroreflex
function. In contrast to scBRS, we observed an almost absent
hypoxic ventilatory response with a nonsignificant blunting of the heart rate response to hypoxia in resected patients
Figure 3. Changes in heart rate, blood pressure, and baroreflex sensitivity during hypoglycemia. In control subjects, heart rate increased
during hypoglycemia (A, †P<0.01 vs baseline) and blood pressure was maintained at baseline levels (B, P>0.05). Hypoglycemia-mediated
reductions in blood pressure were observed in carotid body–resected patients (B, †P<0.05 vs baseline), although a rise in heart rate was
not apparent (A, *P<0.05 vs control). scBRS was reduced from baseline during hypoglycemia (†P<0.01) and was lower in carotid body–
resected patients when compared with controls (*P<0.05). Data are presented as group averages of the slope of the relationship between
heart rate and systolic blood pressure (C, R–R interval [ms] and systolic blood pressure [mm Hg]; D, heart rate [bpm] and systolic blood
pressure [mm Hg]).
Limberg et al Carotid Body Resection and Baroreflex Control 1369
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
the carotid chemoreceptors. For example (1) transient blockade of peripheral chemoreceptors with hyperoxia temporarily
increases baroreflex sensitivity in patients with heart failure,2
(2) unilateral carotid body resection in a human heart failure
patient resulted in an improvement in baroreflex sensitivity,23 and (3) activation of the peripheral chemoreceptors with
hypoxia decreases baroreflex sensitivity.4 In addition, previous
studies have shown antecedent hypoglycemia to reduce baroreflex sensitivity24 and reset the baroreflex working range.25
Our laboratory has recently shown the baroreflex working
range is reset to higher heart rates such that SBP is relatively
maintained during hypoglycemia.5 By contrast, when the
carotid chemoreceptors are acutely desensitized with systemic hyperoxia, there is a significant reduction in blood pressure and a blunted rise in heart rate compared with normoxic
conditions. Given these changes were assessed in otherwise
healthy adults, using acute (≈3 hours) hyperoxia to desensitize
the carotid chemoreceptors, we sought to examine baroreflex
sensitivity during hypoglycemia in patients after permanent
bilateral carotid body resection. This has important clinical
implications, given carotid body resection has emerged as a
potential therapeutic target for the treatment of sympathoexcitatory conditions.10
Surprisingly, both the groups (control and patients) exhibited a reduction in scBRS with hypoglycemia (Figure 3C and
3D). In healthy controls, this fall in scBRS was accompanied
with a shift in the operating point to higher heart rates such
that SBP was preserved (Table 2; Figure 3). However, carotid
body–resected patients exhibited a large reduction in both
SBP (−17±7 mm Hg) and mean (−14±5 mm Hg) blood pressure and a blunted rise in heart rate under hypoglycemic conditions (Table 2; Figure 3). These data demonstrate that intact
carotid chemoreceptors are essential for increasing heart rate
and maintaining arterial blood pressure within normal ranges
during physiological stress in humans.
Figure 4. Changes in blood pressure distribution with
hypoglycemia. An increase in blood pressure distribution (%
coefficient of variation [CV] of systolic blood pressures) with
hypoglycemia was not observed (A, *main effect of group,
P=0.05; main effect of time, P=0.46; interaction of group and
time, P=0.52). Blood pressure distribution is also shown as a
frequency distribution curve (B, control subjects; C, resected
subjects).
(Figure 1). These data are in agreement with findings from
Niewinski et al,8 who have shown carotid body resection in
patients with heart failure significantly blunts the ventilatory
response, but not the heart rate response, to hypoxia. It is likely
the response to hypoxia is mediated by multiple chemoreceptive sites; whereas the carotid bodies play a role in the ventilatory response to hypoxia, it seems the heart rate response may
be mediated by another site (eg, the aortic bodies or perhaps a
site in the central nervous system).
Cardiac Baroreflex Control During Hypoglycemia
In response to a transient fall in blood pressure, the baroreceptors initiate reflex increases in heart rate to maintain blood
pressure at optimal levels. However, baroreflex control of
blood pressure may be altered by inhibition or activation of
Experimental Considerations
Given the complexity of the study design, data from a previously published cohort of younger adults5,11 were used to
compare between healthy adults (25±1 years) and carotid
body–resected patients (40±5 years). Although the age difference may explain higher baseline heart rates between groups
(relationship between resting heart rate and age: r=0.549;
P=0.03), we feel this does not affect our major findings for
the following reasons: (1) the relatively limited number of
resected patients inflates an otherwise small age difference, (2)
the majority of research showing an age-effect on baroreflex
sensitivity has been conducted in adults of an older age range
(60+) compared with the middle-aged subjects studied (28–55
years),26 (3) the patients we studied are generally healthy, and
(4) the observed baroreflex sensitivity in both the groups is
similar to previously published levels from other healthy control groups.26 However, it is important to point out that while
we interpret our results as preserved baseline baroreflex sensitivity (Figure 2), we may have actually observed an increase
in the patients from presurgical levels. This finding is at odds
with data suggesting carotid body resection or desensitization
with dopamine impairs baroreflex sensitivity7,27 but is consistent with other observations showing carotid body resection or
1370 Hypertension June 2015
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
acute chemoreceptor desensitization with hyperoxia improves
baroreflex sensitivity.2,23
Hypoglycemia is achieved experimentally in humans
through the use of a hyperinsulinemic clamp. Thus, it is
important to acknowledge insulin may work at the level of the
carotid body glomus cells to increase chemoreceptor-mediated
afferent activity independent of hypoglycemia.28,29 In addition,
insulin results in peripheral vasodilation, and in adults with
autonomic failure, intravenous insulin infusion results in a
reduction in blood pressure.30 However, given Young et al31
observed no effect of hyperinsulinemia alone on scBRS, any
change in scBRS observed in this study is unlikely to be the
result of hyperinsulinemia alone.
Spontaneous baroreflex sensitivity provides an estimate of
the baroreflex sensitivity at the level of the operating point,
thus it is possible that the observed reduction in baroreflex
sensitivity with hypoglycemia is, rather than a reduction in
scBRS, the result of a shift in the operating point. In addition, we examined the effect of hypoglycemia and carotid
body resection on cardiac baroreflex sensitivity, however,
the differential effect of hypoglycemia on SBP and diastolic
blood pressure (Table 2) supports the idea of differing efferent pathways. Thus, it is possible activation of the carotid
chemoreceptors with hypoglycemia increases sinus nerve
afferent activity directed toward the nucleus tractus solitarius
that differentially affects the vagus (heart rate and SBP) and
rostral ventrolateral medulla (sympathetic activity, and diastolic blood pressure). The lack of corresponding increase in
blood pressure variability (Figure 4) with reductions in scBRS
(Figure 3) may support this point. Direct measures of sympathetic activity will be needed to address this issue.
Perspectives
Carotid body resection has recently been identified as a potential therapeutic strategy for diseases, such as heart failure and
hypertension.10 However, concern exists about possible longterm effects of chronic denervation procedures. In this way,
understanding the role of the carotid chemoreceptors in the
integrated blood pressure responses to hypotensive stimuli
will be a key before targeting these receptors for therapeutic interventions. Data from this study suggest that impaired
blood pressure responses to physiological stressors may occur
after carotid body denervation without the presence of overt
baroreceptor failure. This observation raises the possibility
that there may be unforeseen autonomic consequences of
carotid body denervation, even in relatively healthy adults.
Acknowledgments
We appreciate and thank our research participants and Dr William
Young and his staff from the Mayo Clinic Division of Endocrinology
for assistance in subject recruiting. We also thank Dr John Eisenach,
Cheryl Shonkwiler, Barbara Norby, Shelly Roberts, Karen Krucker,
Sarah Wolhart, Jean Knutson, Brent McConahey, Pamela Reich,
Nancy Meyer, Pam Engrav, and Christopher Johnson of the Mayo
Clinic. Additionally, we thank the Clinical Research Unit staff and
the Immunochemical Core Laboratory (Hilary Blair) at the Mayo
Clinic.
Sources of Funding
This study was supported by National Institutes of Health (NIH)
DK090541 (M.J. Joyner, R. Basu), NIH NS32352 (M.J. Joyner), NIH
T32 DK07352 (E.A. Wehrwein, J.K. Limberg), NIH F32 DK84624
(E.A. Wehrwein), NIH F32 HL120570 (J.K. Limberg), NIH 1 UL1
RR024150 (Mayo Clinic CTSA, M.J. Joyner), and NIH DK29953
(R. Basu).
Disclosures
None.
References
1. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans.
J Clin Invest. 1991;87:1953–1957. doi: 10.1172/JCI115221.
2.Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Peploe K,
Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G,
Giordano A, Coats AJ. Augmented peripheral chemosensitivity as a
potential input to baroreflex impairment and autonomic imbalance in
chronic heart failure. Circulation. 1997;96:2586–2594.
3. Despas F, Lambert E, Vaccaro A, Labrunee M, Franchitto N, Lebrin M,
Galinier M, Senard JM, Lambert G, Esler M, Pathak A. Peripheral chemoreflex activation contributes to sympathetic baroreflex impairment
in chronic heart failure. J Hypertens. 2012;30:753–760. doi: 10.1097/
HJH.0b013e328350136c.
4.Cooper VL, Pearson SB, Bowker CM, Elliott MW, Hainsworth R.
Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and
hypercapnia - a mechanism for promoting hypertension in obstructive sleep
apnoea. J Physiol. 2005;568:677–687. doi: 10.1113/jphysiol.2005.094151.
5. Limberg JK, Taylor JL, Dube S, Basu R, Basu A, Joyner MJ, Wehrwein
EA. Role of the carotid body chemoreceptors in baroreflex control of blood
pressure during hypoglycaemia in humans. Exp Physiol. 2014;99:640–
650. doi: 10.1113/expphysiol.2013.076869.
6. Wade JG, Larson CP Jr, Hickey RF, Ehrenfeld WK, Severinghaus JW.
Effect of carotid endarterectomy on carotid chemoreceptor and baroreceptor function in man. N Engl J Med. 1970;282:823–829. doi: 10.1056/
NEJM197004092821501.
7.Timmers HJ, Karemaker JM, Wieling W, Marres HA, Folgering HT,
Lenders JW. Baroreflex and chemoreflex function after bilateral carotid
body tumor resection. J Hypertens. 2003;21:591–599. doi: 10.1097/01.
hjh.0000052471.40108.95.
8. Niewinski P, Janczak D, Rucinski A, Tubek S, Engelman ZJ, Jazwiec P,
Banasiak W, Sobotka PA, Hart EC, Paton JF, Ponikowski P. Dissociation
between blood pressure and heart rate response to hypoxia after bilateral
carotid body removal in men with systolic heart failure. Exp Physiol.
2014;99:552–561. doi: 10.1113/expphysiol.2013.075580.
9. Lugliani R, Whipp BJ, Seard C, Wasserman K. Effect of bilateral carotidbody resection on ventilatory control at rest and during exercise in man. N
Engl J Med. 1971;285:1105–1111. doi: 10.1056/NEJM197111112852002.
10. Paton JF, Sobotka PA, Fudim M, Engelman ZJ, Engleman ZJ, Hart EC,
McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell
A, Ratcliffe L, Nightingale A. The carotid body as a therapeutic target
for the treatment of sympathetically mediated diseases. Hypertension.
2013;61:5–13. doi: 10.1161/HYPERTENSIONAHA.111.00064.
11.Wehrwein EA, Basu R, Basu A, Curry TB, Rizza RA, Joyner MJ.
Hyperoxia blunts counterregulation during hypoglycaemia in humans:
Possible role for the carotid bodies? J Physiol. 2010;588:4593–4601. doi:
10.1113/jphysiol.2010.197491
12. Wehrwein EA, Limberg JK, Taylor JL, Dube S, Basu A, Basu R, Rizza
RA, Curry TB, Joyner MJ. Effect of bilateral carotid body resection on
the counterregulatory response to hypoglycaemia in humans. Exp Physiol.
2015;100:69–78. doi: 10.1113/expphysiol.2014.083154.
13. Halliwill JR, Morgan BJ, Charkoudian N. Peripheral chemoreflex and
baroreflex interactions in cardiovascular regulation in humans. J Physiol.
2003;552:295–302. doi: 10.1113/jphysiol.2003.050708.
14.Masuki S, Eisenach JH, Dinenno FA, Joyner MJ. Reduced forearm
alpha1-adrenergic vasoconstriction is associated with enhanced heart rate
fluctuations in humans. J Appl Physiol (1985). 2006;100:792–799. doi:
10.1152/japplphysiol.00586.2005.
15. Cowley AW Jr, Liard JF, Guyton AC. Role of baroreceptor reflex in daily
control of arterial blood pressure and other variables in dogs. Circ Res.
1973;32:564–576.
16. Smit AA, Timmers HJ, Wieling W, Wagenaar M, Marres HA, Lenders
JW, van Montfrans GA, Karemaker JM. Long-term effects of carotid
sinus denervation on arterial blood pressure in humans. Circulation.
2002;105:1329–1335.
Limberg et al Carotid Body Resection and Baroreflex Control 1371
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
17. Robertson D, Hollister AS, Biaggioni I, Netterville JL, Mosqueda-Garcia
R, Robertson RM. The diagnosis and treatment of baroreflex failure. N Engl
J Med. 1993;329:1449–1455. doi: 10.1056/NEJM199311113292003.
18. De Toma G, Nicolanti V, Plocco M, Cavallaro G, Letizia C, Piccirillo G,
Cavallaro A. Baroreflex failure syndrome after bilateral excision of carotid
body tumors: an underestimated problem. J Vasc Surg. 2000;31:806–810.
doi: 10.1067/mva.2000.103789.
19. Holton P, Wood JB. The effects of bilateral removal of the carotid bodies
and denervation of the carotid sinuses in two human subjects. J Physiol.
1965;181:365–378.
20. Sleight P. Neurophysiology of the carotid sinus receptors in normal and
hypertensive animals and man. Cardiology. 1976;61(suppl 1):31–45.
21. Palatini P, Pessina AC, Casiglia E, Sperti G, Mormino P, Di Marco A, Ventura E,
Gava R, Dal Palù C. Evaluation of blood pressure control after bilateral glomectomy: effects of propranolol treatment. Clin Physiol Biochem. 1987;5:320–328.
22. Timmers HJ, Wieling W, Karemaker JM, Lenders JW. Denervation of
carotid baro- and chemoreceptors in humans. J Physiol. 2003;553:3–11.
doi: 10.1113/jphysiol.2003.052415.
23. Niewiński P, Janczak D, Rucinski A, Jazwiec P, Sobotka PA, Engelman
ZJ, Fudim M, Tubek S, Jankowska EA, Banasiak W, Hart EC, Paton JF,
Ponikowski P. Carotid body removal for treatment of chronic systolic heart
failure. Int J Cardiol. 2013;168:2506–2509. doi: 10.1016/j.ijcard.2013.03.011.
24.Adler GK, Bonyhay I, Failing H, Waring E, Dotson S, Freeman R.
Antecedent hypoglycemia impairs autonomic cardiovascular function:
implications for rigorous glycemic control. Diabetes. 2009;58:360–366.
doi: 10.2337/db08-1153.
25. Fagius J, Berne C. Rapid resetting of human baroreflex working range:
insights from sympathetic recordings during acute hypoglycaemia. J
Physiol. 1991;442:91–101.
26. Davy KP, DeSouza CA, Jones PP, Seals DR. Elevated heart rate variability in physically active young and older adult women. Clin Sci (Lond).
1998;94:579–584.
27. Niewinski P, Tubek S, Banasiak W, Paton JF, Ponikowski P. Consequences
of peripheral chemoreflex inhibition with low-dose dopamine in humans.
J Physiol. 2014;592:1295–1308. doi: 10.1113/jphysiol.2013.266858.
28. Limberg JK, Curry TB, Prabhakar NR, Joyner MJ. Is insulin the new
intermittent hypoxia? Med Hypotheses. 2014;82:730–735. doi: 10.1016/j.
mehy.2014.03.014.
29.Ribeiro MJ, Sacramento JF, Gonzalez C, Guarino MP, Monteiro EC,
Conde SV. Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets. Diabetes.
2013;62:2905–2916. doi: 10.2337/db12-1463.
30. Brown RT, Polinsky RJ, Baucom CE. Euglycemic insulin-induced hypotension in autonomic failure. Clin Neuropharmacol. 1989;12:227–231.
31.Young CN, Deo SH, Chaudhary K, Thyfault JP, Fadel PJ. Insulin
enhances the gain of arterial baroreflex control of muscle sympathetic
nerve activity in humans. J Physiol. 2010;588:3593–3603. doi: 10.1113/
jphysiol.2010.191866.
Novelty and Significance
What Is New?
• We examined hypoglycemia-mediated changes in baroreflex control of
heart rate in subjects with limited neural input from the carotid chemoreceptors as a result of bilateral surgical removal of these organs for carotid body glomus tumors. Despite relatively normal baroreflex function
at baseline, we found the absence of carotid body chemoreceptors limits
blood pressure regulation during hypoglycemia.
What Is Relevant?
• In addition to furthering our understanding of carotid chemoreflex and
baroreflex interactions, these findings have therapeutic implications
b­ ecause carotid body resection has recently emerged as a potential
strategy for the treatment of sympathoexcitatory conditions.
Summary
Hypoglycemia results in a reduction in cardiac baroreflex sensitivity
and a shift in the baroreflex working range to higher heart rates;
this effect is mediated, in part, by the carotid chemoreceptors.
Effect of Bilateral Carotid Body Resection on Cardiac Baroreflex Control of Blood
Pressure During Hypoglycemia
Jacqueline K. Limberg, Jennifer L. Taylor, Michael T. Mozer, Simmi Dube, Ananda Basu, Rita
Basu, Robert A. Rizza, Timothy B. Curry, Michael J. Joyner and Erica A. Wehrwein
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
Hypertension. 2015;65:1365-1371; originally published online April 13, 2015;
doi: 10.1161/HYPERTENSIONAHA.115.05325
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/65/6/1365
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/