(Circulation. 2000;102:2611.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Severely Impaired Baroreflex-Buffering in Patients With Monogenic Hypertension and Neurovascular Contact
From the Clinical Research Center, Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt-University, and the Department of Endocrinology, Klinikum Benjamin Franklin, Free University, Berlin, and the Department of Internal Medicine and Nephrology and Department of Neurosurgery, Friedrich-Alexander University, Erlangen, Germany; and the Autonomic Dysfunction Service, Vanderbilt University, Nashville, Tenn.
Correspondence to Jens Jordan, MD, Clinical Research Center, Franz-Volhard-Clinic, Humboldt University, Wiltbergstraße 50, 13125 Berlin, Germany. E-mail jordan{at}fvk-berlin.de
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Abstract |
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Background—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and neurovascular contact of the brain stem. Neurovascular contact of the ventrolateral medulla may lead to arterial hypertension by interfering with baroreflex function.
Methods and Results—In 5 patients with monogenic hypertension (18 to 34 years old), we conducted detailed autonomic function tests. Blood pressure during complete ganglionic blockade was 134±4.9/82±4.1 mm Hg and 90±6/49±2.4 mm Hg in patients and in control subjects, respectively. During ganglionic blockade, plasma vasopressin concentration increased 24-fold in control subjects and <2-fold in patients. In patients, cold pressor testing, hand-grip testing, and upright posture all increased blood pressure excessively. In contrast, muscle sympathetic nerve activity was not increased at rest or during cold pressor testing. The phenylephrine dose that increased systolic blood pressure 12.5 mm Hg was 8.0±2.0 µg in patients and 135±35 µg in control subjects before ganglionic blockade and 5.4±0.4 µg in patients and 13±4.8 µg in control subjects during ganglionic blockade.
Conclusions—In patients with monogenic hypertension and neurovascular contact, basal blood pressure was increased even during sympathetic and parasympathetic nerve traffic interruption. However, sympathetic stimuli caused an excessive increase in blood pressure. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that baroreflex buffering and baroreflex-mediated vasopressin release are severely impaired.
Key Words: baroreceptors • genetics • hypertension • nervous system, autonomic • receptors
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Introduction |
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Bilginturan et al1 first described autosomal dominant hypertension and brachydactyly. The gene responsible for the syndrome was mapped to chromosome 12p2 . Affected individuals exhibit a profoundly accelerated increase in blood pressure with age.3 We showed earlier that affected individuals are not salt sensitive and that plasma renin activity and aldosterone respond normally to volume expansion and depletion.3 We subsequently showed by MR tomography that all 15 affected family members tested had a left-sided loop of the posterior inferior cerebellar artery (PICA) impinging on the rostroventrolateral medulla, compared with none of 11 nonaffected family members.4 Pulsatile compression of the rostroventrolateral medulla may contribute to essential hypertension.5 6 This hypothesis is supported by the observation that neurosurgical decompression of the brain stem improves blood pressure control.7 Animal studies suggest that pulsatile compression of the rostroventrolateral medulla increases blood pressure through sympathetic activation.8 Whether similar autonomic abnormalities occur in humans is not known. We tested the hypothesis that in patients with monogenic hypertension, brachydactyly, and neurovascular contact, the hypertension is mediated through sympathetic activation. Furthermore, we tested whether these changes were caused by increased sympathetic nerve traffic, increased vascular sensitivity, or impaired baroreflex buffering.
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Methods |
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Subjects
Five younger family members with hypertension and brachydactyly traveled to Germany to participate in this study (3 men, 2 women, 26±3.4 years old, 57±4.0 kg, 152±2.4 cm tall). Their results were compared with those of healthy normotensive control subjects of similar age. Written informed consent was obtained. All studies were approved by the institutional review board.
Protocol
Three days before the study, volunteers received a
150-mmol sodium diet free of substances that could interfere with
catecholamine measurements. All vasoactive medications were
discontinued 
5 half-lives before testing. The patients underwent a
physical examination, MRI imaging of the brain
stem,4 and a series
of autonomic tests on separate days.
Posture Study
After the patients had remained overnight in the supine
position, venous samples for plasma renin activity and aldosterone
concentrations were obtained from a heparin lock placed 30 minutes
before the first blood draw. Blood samples were again obtained after 30
minutes in the standing position. Automated measurements of
blood pressure and heart rate were made (Dinamap, Criticon). On a
separate day, the study was repeated after an intravenous infusion of
1000 mL normal saline in 30 minutes.
Autonomic Reflex Testing
Sinus arrhythmia was assessed during controlled
breathing (5-second inhalation and 5-second exhalation for 90 seconds).
The sinus arrhythmia ratio was calculated as the ratio of the longest
to the shortest RR interval during these 90 seconds. Patients performed
a Valsalva maneuver (40 mm Hg pressure for 15 seconds). Blood pressure
and heart rate responses to isometric handgrip (30% maximum
contraction for 1 minute) and cold pressor testing were also
determined.9
Pharmacological testing was conducted with the subject
recumbent 2.5 hours after the last meal. Heart rate was determined
with a continuous ECG, blood pressure by an indwelling catheter in the
radial artery, and changes in stroke volume by impedance
cardiography.10 Leg
blood flow was determined before and during complete ganglionic
blockade by occlusion plethysmography (EC 5R, Hokanson). Responses to
incremental intravenous bolus doses of nitroprusside and phenylephrine
were evaluated before ganglionic blockade. Thereafter, we infused the
ganglionic blocker trimethaphan (Cambridge Pharmaceuticals) starting at
1 mg/min and increasing at 6-minute intervals until the efferent arc of
the baroreflex was completely
blocked.11 Bolus
doses of phenylephrine were then administered just as before
blockade.
The baroreflex slope was determined at the linear portion of the sigmoidal relation between phenylephrine-induced blood pressure changes and changes in RR interval. The spontaneous baroreflex slope was determined by the sequence technique.12 The doses of each drug that would change blood pressure by 12.5 mm Hg were determined by extrapolation from individual dose-response curves.
Microneurography
During the microneurography study, heart rate was
determined by continuous ECG and beat-by-beat blood pressure by
photoplethysmography (Finapres, Ohmeda). Microneurography recordings
were obtained as described
previously.13
Analytical Methods
Plasma and urinary catecholamines were determined by a
modification of a high-performance liquid chromatographic
method.14 Plasma
vasopressin concentration was determined by a
radioimmunoassay.
Statistics
All data are expressed as mean±SEM. Intraindividual
and interindividual differences were compared by paired and unpaired
t tests, respectively. ANOVA testing for repeated
measures was used for multiple comparisons. If necessary, data were
logarithmically transformed before analysis. Relationships between
parameters were assessed by linear regression analysis. A value of
P<0.05 was considered significant.
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Results |
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Clinical Characteristics
All 5 patients had severe arterial hypertension. None had cardiovascular complications. All had a normal creatinine clearance, and none had microalbuminuria. Echocardiography showed normal systolic function. One patient had mild left ventricular hypertrophy. However, none had signs of impaired left ventricular filling. MRI of the brain stem showed a left-sided loop of the PICA in all affected subjects (Figure 1
).4
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Posture Studies and Catecholamines
Figure 2 illustrates supine and upright blood pressure and
heart rate. Without volume loading, blood pressure was 135±6.7/81±4.6
mm Hg and increased to 148±3.2/99±5.7 mm Hg after 5 minutes in the
standing position (P=0.1 for systolic blood pressure
and P=0.01 for diastolic blood pressure). This
increase in blood pressure was associated with a change in heart rate
from 59±3.2 bpm supine to 87±5.5 bpm upright. Before volume loading,
supine blood pressure was 140±6.0/84±6.0 mm Hg and supine heart rate
was 63±4 bpm. Immediately after volume loading, supine blood pressure
was 140±5.8/84±4.0 mm Hg and supine heart rate was 66±5.0 bpm. With
volume loading, the increase in blood pressure with standing was
attenuated. After 5 minutes of standing, blood pressure was
141±3.9/94±4.4 mm Hg and heart rate was 71±4.2 bpm. Plasma
norepinephrine and epinephrine concentrations were not excessively
increased in the supine or upright position
(Table).
Urinary excretion of norepinephrine was 112±24 nmol/d (normal range
136 to 621 nmol/d). Urinary epinephrine excretion was 38±8.2 nmol/d
(normal range 22 to 109 nmol/d).
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Autonomic Reflex Testing
Respiratory sinus arrhythmia was
1.3±0.055. During Valsalva maneuver phase II, blood pressure
increased 12±11/26±9.8 mm Hg. Blood pressure increased
45±12/24±6.3 mm Hg during phase IV. The Valsalva heart rate ratio
was 1.4±0.19. With hand-grip testing, blood pressure increased
36±5.0/24±2.7 mm Hg. After 1 minute of cold pressor testing, blood
pressure increased 46±8.8/27±5.5 mm Hg. In 4 patients, blood
pressure increased profoundly with cold pressor testing (range 45 to
66/22 to 41 mm Hg); 1 patient had a clearly abnormal response (9/7
mm Hg change) but had no pain during the test. The pressor responses
to hand-grip exercise and to cold were exaggerated compared with
control
subjects.15
Responses to Complete Ganglionic
Blockade
Before trimethaphan infusion, blood pressure was
150±4.9/86±1.8 mm Hg and heart rate was 67±6.3 bpm.
Figure 3 illustrates changes in blood pressure, heart rate,
and stroke volume with increasing trimethaphan infusion. When complete
ganglionic blockade was achieved, blood pressure and heart rate were
134±4.9/82±4.1 mm Hg and 90±2.6 bpm, respectively. In control
subjects,15 blood
pressure in the supine position was 129±4.0/65±3.0 mm Hg before
trimethaphan. With complete ganglionic blockade, blood pressure
decreased to 90±6/49±2.4 mm Hg (P<0.01 compared
with patients). Decreases in both systolic (P<0.05)
and diastolic blood pressure (P<0.01) were smaller in
patients than in control subjects. In patients, the decrease in blood
pressure was associated with a 7.5±5.3% decrease in cardiac output.
Stroke volume decreased 31±5.0%. Leg blood flow increased from
5.9±0.6 mL·100
mL-1·s-1 at
baseline to 11±2 mL·100
mL-1·s-1 during
complete ganglionic blockade. Plasma norepinephrine concentration
decreased profoundly during ganglionic blockade
(Table
).
In patients, plasma vasopressin concentration was 0.47±0.02 pg/mL at
baseline and 0.84±0.13 pg/mL during complete ganglionic blockade
(Figure 4). In control subjects, in contrast, plasma
vasopressin concentration increased profoundly during ganglionic
blockade (1.6±0.17 pg/mL at baseline, 39±13 pg/mL during ganglionic
blockade).
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Sensitivity to Phenylephrine and Nitroprusside
and Baroreflex Slope
Before ganglionic blockade, patients were extremely
hypersensitive to the pressor effect of phenylephrine
(Figure 5). The phenylephrine dose that increased systolic
blood pressure 12.5 mm Hg was 8.0±2.0 µg in patients and 135±35
µg in control subjects
(Figure 6). During ganglionic blockade, the phenylephrine
dose that increased systolic blood pressure 12.5 mm Hg was 5.4±0.4
µg in patients and 13±4.8 µg in control subjects
(P<0.0001 between groups, P<0.001
between interventions, P<0.01 for the interaction
between group and intervention). Ganglionic blockade potentiated the
pressor effect by factors of 1.5±0.5 and 15±4.3 in patients and
control subjects, respectively (P<0.01). Without
ganglionic blockade, patients were hypersensitive to the depressor
effect of nitroprusside
(Figure 7). The nitroprusside dose that decreased systolic
blood pressure 12.5 mm Hg without ganglionic blockade was 0.20±0.066
µg/kg in patients and 1.8±0.50 in control subjects
(P<0.01)
(Figure 8). The baroreflex slope determined by phenylephrine
bolus application was 9.4±1.6 ms/mm Hg. Baroreflex slope determined
by the sequence technique was 12±2.0 ms/mm Hg. In 3 patients,
baroreflex slope was above the 90th percentile for age, and in 2
patients, it was between the 90th and 95th
percentiles.12
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Microneurography
Representative microneurography recordings are
illustrated in
Figure 9. Baseline sympathetic activity in the supine
position was 15±4.6 bursts/min. In a previous study, resting muscle
sympathetic nerve activity was 12±6 bursts/min in young normotensive
control subjects and 14±9 bursts/min in young borderline
hypertensives.13
Microneurography incidence was 22±6.5 bursts/100 heartbeats. With cold
pressor testing, muscle sympathetic nerve activity increased 7.5±6.8
bursts/min (11±10 bursts/100 heartbeats). By comparison, cold pressor
testing elicited an increase in muscle sympathetic nerve activity by
14±10 bursts/min in normotensive control subjects and by 11±8.0
bursts/min in patients with borderline
hypertension.13 With
lower-body negative pressure, muscle sympathetic nerve activity
increased from 19±5.8 bursts/min (31±8.6 bursts/100 heartbeats) at 0
mm Hg to 24±6.5 bursts/min (36±9.0 bursts/100 heartbeats) at -10
mm Hg suction (n=4). This increase in sympathetic nerve traffic during
lower-body negative pressure was associated with a decrease in forearm
blood flow from 8.7±1.4 mL/100 mL to 6.6±0.8 mL/100 mL. Blood
pressure was 131±4.6/74±2.6 mm Hg at 0 mm Hg and 134±3.3/76±2.0
mm Hg at -10 mm Hg lower-body negative
pressure.
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Discussion |
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Our main finding was that in patients with monogenic hypertension, brachydactyly, and neurovascular contact, blood pressure during complete ganglionic blockade was 44 mm Hg greater than in control subjects. However, sympathetic stimuli caused an excessive increase in blood pressure. This increase was not due to increased sympathetic nerve traffic. The patients were extremely hypersensitive to phenylephrine and nitroprusside. With ganglionic blockade, the pressor effect of phenylephrine was only slightly augmented in patients but increased dramatically in control subjects. Furthermore, with ganglionic blockade, plasma vasopressin concentration increased profoundly in control subjects but changed little in patients.
We used trimethaphan to determine the contribution of autonomic nervous system activity to blood pressure control.16 Ganglionic blockade at the level achieved in this study abolishes sympathetic and parasympathetic modulation of heart rate and blood pressure.15 Even with substantial changes in blood pressure, heart rate does not change and muscle sympathetic nerve activity is abolished.11 The blockade is associated with decreased plasma norepinephrine concentrations as low as seen in patients with severe pure autonomic failure.15 Plasma catecholamines and muscle sympathetic nerve activity were low normal in our patients, suggesting that the sympathetic contribution to supine blood pressure was not increased. In this regard, our patients resemble patients with secondary hypertension rather than patients with essential hypertension.17 Because sympathetic nerve traffic is not evenly distributed throughout the body,18 muscle sympathetic nerve activity may not necessarily reflect overall sympathetic tone. Yet, blood pressure decreased with complete ganglionic blockade to a lesser degree than in control subjects,15 19 which further supports there being no increase in basal sympathetic tone. Blood pressure during ganglionic blockade was still greater in patients than in control subjects. Thus, the increase in basal blood pressure is not entirely explained by sympathetic nervous system activation. We cannot completely exclude chronic sympathetic stimulation and vascular remodeling. Stroke volume, on the other hand, decreased sharply in our patients, which may be due to a decrease in cardiac preload or cardiac contractility.20
Several lines of evidence suggest that the autonomic nervous system contributes to hypertension in our patients. Perhaps the strongest evidence is the profound increase in blood pressure with standing. The increase was attenuated with volume loading, suggesting that the excessive increase in blood pressure was due to overcompensation of a reduction in cardiac preload. Similarly, leg compression prevents the orthostatic increase in blood pressure in patients with orthostatic hypertension.21 Moreover, stimuli such as cold pressor testing and hand-grip exercise led to a greater than normal pressor response. Although blood pressure responses to these stimuli were excessive, the increase in muscle sympathetic nerve activity was moderate. Thus, a smaller increase in sympathetic nerve traffic may elicit a greater pressor response.
If a smaller increase in sympathetic nerve traffic is associated with an excessive pressor response, the amount of norepinephrine with a given stimulus must be increased or the same amount of norepinephrine elicits a greater response. Plasma and urinary norepinephrine concentrations were not increased in our patients, evidence against increased norepinephrine release. Less likely is the explanation that increased norepinephrine release could be masked by changes in norepinephrine clearance.22 Therefore, the same amount of norepinephrine may elicit a greater pressor response. Indeed, our patients were extremely hypersensitive to the phenylephrine pressor response before ganglionic blockade. Ganglionic blockade can be used to study vascular responses in the absence of baroreflex-mediated changes in autonomic tone.11 The fact that the sensitivity to phenylephrine was similar in patients and in control subjects during ganglionic blockade challenges the concept that increased vascular sensitivity underlies the hypersensitivity to phenylephrine.
The most likely explanation for phenylephrine hypersensitivity in our patients is impaired baroreflex buffering. The main purpose of the baroreflexes is to buffer changes in cardiac preload or vascular tone. In patients with damage to the afferent arc (baroreflex failure), the sensitivity to phenylephrine and nitroprusside is dramatically increased.23 Similarly, impaired function of the efferent arc, due to either neuronal degeneration (autonomic failure)24 25 26 27 or ganglionic blockade,11 28 29 causes a profound increase in sensitivity to vasodilators and vasoconstrictors. In our patients, phenylephrine sensitivity was similar to the sensitivities observed in patients with baroreflex failure23 or autonomic failure24 or in control subjects during ganglionic blockade.11 Furthermore, the sensitivity to phenylephrine increased only slightly during complete ganglionic blockade, suggesting that the restraining effect of the autonomic nervous system was profoundly impaired. The finding that plasma vasopressin concentration did not increase despite a marked depressor response is further evidence for impaired baroreflex function.30 31 We15 and others32 have shown that in healthy subjects, ganglionic blockade with trimethaphan leads to a profound baroreflex-mediated increase in vasopressin concentrations. Paradoxically, the baroreflex control of heart rate was only mildly impaired, suggesting that the baroreflex dysfunction involved primarily control of vascular tone and of vasopressin release. The wide spontaneous fluctuations in blood pressure typical for patients with baroreflex failure23 33 were not observed in our patients. These findings suggest that noninvasive or invasive determination of the baroreflex–heart rate slope34 35 does not give sufficient information on baroreflex control of vascular tone and vasopressin release.36 Reliance on this parameter alone in our subjects would have led to faulty conclusions regarding their baroreceptor reflex function.
The location of the lesion to the baroreflex in our patients is difficult. Absence of orthostatic hypotension and the results of autonomic reflex testing suggest that the efferent limb of the baroreflex is at least in part intact. Impaired baroreflex-mediated vasopressin release suggests that the lesion is proximal to sympathetic efferent neurons in the rostroventrolateral medulla. Because baroreflex control of heart rate was only slightly impaired, whereas control of vascular tone was severely affected, we suggest that the lesion must be located at a place where heart rate and blood pressure control are in part separated.
All patients studied and other affected family members had a left-sided vascular PICA loop impinging on the rostroventrolateral medulla, whereas nonaffected family members had no such loops.4 Animal studies have shown that pulsatile compression of the rostroventrolateral medulla exerted by a balloon increases blood pressure, which may be mediated through alteration of afferent neurons traveling from baroreceptors to the nucleus tractus solitarius or through direct activation of efferent sympathetic neurons.8 37 Our study demonstrates that in humans, neurovascular contact of the rostroventrolateral medulla can be associated with baroreflex dysfunction and changes in sympathetic nervous system activation. However, neurosurgical decompression of the brain stem would be necessary to prove a causal relationship between neurovascular contact and baroreflex dysfunction in these patients.5 38 39
We conclude that in patients with monogenic hypertension, brachydactyly, and neurovascular contact of the rostroventrolateral medulla, basal blood pressure was increased even during interruption of sympathetic and parasympathetic nerve traffic. However, sympathetic stimuli such as standing and cold pressor testing caused an excessive increase in blood pressure. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that the ability of the baroreflex to buffer changes in vascular tone is severely impaired in these subjects.
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Acknowledgments |
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This study was supported by a grant-in-aid from AstraZeneca, Wedel, Germany.
Received June 6, 2000; revision received July 5, 2000; accepted July 7, 2000.
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 D. D. Christou, P. Parker Jones, A. E. Pimentel, and D. R. Seals Increased abdominal-to-peripheral fat distribution contributes to altered autonomic-circulatory control with human aging Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1530 - H1537. [Abstract] [Full Text] [PDF]
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J. Tank, A. Diedrich, E. Szczech, F. C. Luft, and J. Jordan {alpha}-2 Adrenergic Transmission and Human Baroreflex Regulation Hypertension, May 1, 2004; 43(5): 1035 - 1041. [Abstract] [Full Text] [PDF]
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S. Bahring, A. Rauch, O. Toka, C. Schroeder, C. Hesse, H. Siedler, G. Fesus, W. E. Haefeli, A. Busjahn, A. Aydin, et al. Autosomal-Dominant Hypertension With Type E Brachydactyly Is Caused by Rearrangement on the Short Arm of Chromosome 12 Hypertension, February 1, 2004; 43(2): 471 - 476. [Abstract] [Full Text] [PDF]
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 F. C. Luft, O. Toka, H. R. Toka, J. Jordan, and S. Bahring Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2003; 285(4): R709 - R714. [Abstract] [Full Text] [PDF]
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 F. C. Luft Mendelian Forms of Human Hypertension and Mechanisms of Disease Clin. Med. Res., October 1, 2003; 1(4): 291 - 300. [Abstract] [Full Text] [PDF]
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J. Jordan, A. Lipp, J. Tank, C. Schroder, M. Stoffels, G. Franke, A. Diedrich, G. Arnold, D. S. Goldstein, A. M. Sharma, et al. Catechol-O-Methyltransferase and Blood Pressure in Humans Circulation, July 23, 2002; 106(4): 460 - 465. [Abstract] [Full Text] [PDF]
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T. Ketch, I. Biaggioni, R. Robertson, and D. Robertson Four Faces of Baroreflex Failure: Hypertensive Crisis, Volatile Hypertension, Orthostatic Tachycardia, and Malignant Vagotonia Circulation, May 28, 2002; 105(21): 2518 - 2523. [Abstract] [Full Text] [PDF]
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P. P. Jones, L. F Shapiro, G. A Keisling, R. A Quaife, and D. R Seals Is autonomic support of arterial blood pressure related to habitual exercise status in healthy men? J. Physiol., April 15, 2002; 540(2): 701 - 706. [Abstract] [Full Text] [PDF]
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P. P. Jones, L. F. Shapiro, G. A. Keisling, J. Jordan, J. R. Shannon, R. A. Quaife, and D. R. Seals Altered Autonomic Support of Arterial Blood Pressure With Age in Healthy Men Circulation, November 13, 2001; 104(20): 2424 - 2429. [Abstract] [Full Text] [PDF]
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P. P. Jones, L. F Shapiro, G. A Keisling, R. A Quaife, and D. R Seals Is autonomic support of arterial blood pressure related to habitual exercise status in healthy men? J. Physiol., April 15, 2002; 540(2): 701 - 706. [Abstract] [Full Text] [PDF]
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J. Jordan, J. Tank, J. R. Shannon, A. Diedrich, A. Lipp, C. Schroder, G. Arnold, A. M. Sharma, I. Biaggioni, D. Robertson, et al. Baroreflex Buffering and Susceptibility to Vasoactive Drugs Circulation, March 26, 2002; 105(12): 1459 - 1464. [Abstract] [Full Text] [PDF]
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