(Circulation. 1998;98:2154-2159.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Chronic Orthostatic Intolerance
A Disorder With Discordant Cardiac and Vascular Sympathetic Control
From the Syncope Service in the Autonomic Dysfunction Unit (M.S., D.R., R.M.-G.) and Division of Clinical Pharmacology (R.F., G.J., D.R., P.H., R.M.-G.), Department of Medicine (D.R., R.M.-G.), Vanderbilt University Medical Center, Nashville, Tenn, and Dipartimento di Bioingegneria, Politecnico di Milano, Milan, Italy (A.P.).
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Abstract |
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Background—Chronic orthostatic intolerance (COI) is a debilitating autonomic condition in young adults. Its neurohumoral and hemodynamic profiles suggest possible alterations of postural sympathetic function and of baroreflex control of heart rate (HR).
Methods and Results—In 16 COI patients and 16 healthy volunteers,
intra-arterial blood pressure (BP), ECG, central venous
pressure (CVP), and muscle sympathetic nerve activity (MSNA) were
recorded at rest and during 75° tilt. Spectral analysis
of RR interval and systolic arterial pressure (SAP)
variabilities provided indices of sympathovagal modulation of the
sinoatrial node (ratio of low-frequency to high-frequency components,
LF/HF) and of sympathetic vasomotor control (LFSAP).
Baroreflex mechanisms were assessed (1) by the slope of the regression
line obtained from changes of RR interval and MSNA evoked by
pharmacologically induced alterations in BP and (2) by the index 
,
obtained from cross-spectral analysis of RR and SAP
variabilities. At rest, HR, MSNA, LF/HF, and LFSAP were
higher in COI patients, whereas BP and CVP were similar in the two
groups. During tilt, BP did not change and CVP fell by the same extent
in the 2 groups; the increase of HR and LF/HF was more pronounced in
COI patients. Conversely, the increase of MSNA was lower in COI than in
control subjects. Baroreflex sensitivity was similar in COI and control
subjects at rest; tilt reduced similarly in both groups.
Conclusions—COI is characterized by an overall enhancement of noradrenergic tone at rest and by a blunted postganglionic sympathetic response to standing, with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These data suggest that in COI, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.
Key Words: syncope • baroreceptors • blood pressure • norepinephrine • nervous system, autonomic
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Introduction |
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Chronic orthostatic intolerance (COI) is a disabling syndrome, characterized by pronounced tachycardia and symptoms such as fatigue, lightheadedness, dizziness, palpitations, and rarely syncope, most commonly during the upright position.1 2 3 This condition represents one of the most frequent autonomic disorders in young subjects, and it has been described by myriad terms, including postural orthostatic tachycardia,2 hyperadrenergic orthostatic tachycardia,3 idiopathic hypovolemia,4 and hyperadrenergic orthostatic hypotension.5
Potential pathophysiological mechanisms in COI include a ß-adrenergic hypersensitivity,6 decreased plasma volume,4 7 an inappropriate venous pooling,8 and possible dysautonomia.1 9 The finding of increased plasma catecholamines at rest10 and during standing1 9 10 11 in patients with COI has led to the hypothesis of an abnormally enhanced sympathetic drive to the cardiovascular system as a final common pathophysiological mechanism. In addition, the exaggerated increase of heart rate (HR) in the absence of discernible changes in blood pressure (BP) during standing raises the possibility that abnormalities in the baroreflex control of HR might result in an inappropriate tachycardia.
To the best of our knowledge, there are no studies in which muscle sympathetic nerve activity (MSNA) has been recorded and the cardiac autonomic modulation concomitantly estimated in subjects affected by COI. Direct assessment of these variables is crucial if possible abnormalities in the distribution of autonomic control to the heart and vasculature are to be addressed. The aim of this study was to assess the autonomic profile of patients affected by COI while they were recumbent and during orthostatic stress, including evaluation of baroreflex control of HR and MSNA.
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Methods |
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This study was performed in 16 patients with COI (11 women, 5 men; age, 35±2 years) and in 16 healthy control subjects (7 women, 9 men; age, 30±2 years). Patients underwent a complete medical evaluation to exclude secondary causes of orthostatic intolerance or any other relevant medical condition. Their clinical features are presented in Table 1
. Drug treatment was discontinued
for at least 10 days before the study.
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Subjects with COI were included in this study if they had (1) sustained increase of HR of at least 30 bpm or HR >120 bpm during standing, (2) absence of orthostatic hypotension (falls in systolic/diastolic BP during standing <10 mm Hg), (3) duration of symptoms longer than 6 months, and (4) daily occurrence of at least 2 of the following symptoms: palpitations, dizziness, fatigue, lightheadedness, presyncope, or syncope during upright posture.
Instrumentation Procedure and Recorded Variables
In every subject, we recorded a surface ECG and
intra-arterial BP from the radial artery of the nondominant
arm. In 10 COI patients and 14 control subjects, central venous
pressure (CVP) was measured by means of a microtip pressure transducer
(Millar Instruments Inc) located near the right atrium. Respiratory
activity was monitored by means of thoracic bellows.
In both groups, MSNA was obtained with microneurography as described elsewhere.12 Systemic BP, ECG, CVP, integrated MSNA, and the respiratory signals were digitized at 300 samples per second and stored onto the hard disk of a personal computer for subsequent analysis. Plasma epinephrine and norepinephrine were measured on venous blood.13
Protocol
The experimental protocol was approved by the Vanderbilt
University Institutional Review Board in Human Research. After signing
an informed consent, all subjects received a controlled
methylxanthine-free diet containing 150 mEq of sodium and 80 mEq of
potassium for at least 4 days preceding the study. The day of the
study, the subjects were placed on a motorized tilt-table with a
footrest and underwent instrumentation as described above. Thirty
minutes after instrumentation, baseline data acquisition was initiated
and a blood sample obtained for plasma catecholamines.
Then, subjects were tilted at 15° intervals every 3 minutes until the
75° head-up position was reached. This position was maintained for a
total of 30 minutes. A second blood sample was taken at minute 5 of the
75° tilt.
After the subjects returned to the supine position and after a 30-minute recovery period, we performed the pharmacological evaluation of baroreflex function. All the subjects received incremental doses (lasting 3 minutes) of phenylephrine or sodium nitroprusside (range, 0.1 to 2.4 µg · kg-1 · min-1) in a random fashion. Drug infusion was stopped when systolic BP increased or decreased by 25 mm Hg.
Data Analysis
Microneurography was considered to reflect MSNA according
to criteria previously established.14
Satisfactory recordings of MSNA during the entire procedure
were obtained in 11 COI patients and 14 control subjects. CVP values
are nominal, that is, referenced to atmospheric pressure; because
intrathoracic esophageal pressure was not estimated concomitantly, no
atrial transmural pressure values are provided.
The principles of the software for automatic evaluation of data
and for autoregressive spectral and cross-spectral analysis
have been described elsewhere.15 16 There are 2
main oscillatory components, the amplitude of which is affected by
changes in neural autonomic control.15 16 17 One is
high frequency (HF, 
0.25 Hz at rest). If extracted from RR interval
variability, HFRR provides an index of the vagal
efferent modulation of the sinoatrial node
discharge.18 The other oscillatory component is
indicated as low frequency (LF, 0.1 Hz). In the case of
systolic arterial pressure (SAP) variability,
LFSAP can be considered a marker of the
sympathetic modulation of vasomotor activity.16
The LF component of RR variability (LFRR), when
expressed in normalized units (NU), might reflect primarily the
sympathetic efferent modulation of the sinoatrial (SA) node and its
changes.19 20 21 Normalization is achieved by
dividing the absolute power of each component by total variance (minus
the power of the very-low-frequency component) and subsequently
multiplying by 100.15 The
LFRR/HFRR ratio, which is
independent of units of measure, may furnish a further index reflecting
cardiac sympathovagal balance.15 16 However, as a
ratio, LF/HF may undergo large modifications when the denominator is
markedly lower than the numerator, thus emphasizing even small changes
in the sympathovagal balances. Cross-spectral analysis between
respiration and RR and SAP variabilities was performed because this
allowed the identification of the respiratory-linked fluctuation in the
different power spectra.22
Baroreflex function was assessed by (1) the index , obtained by use
of cross-spectral analysis of RR and SAP spontaneous
oscillations both at rest and during the tilt maneuver; it
was computed as the square root of the ratio between the powers of
corresponding spectral components of RR interval and SAP
variabilities.23 A high level of coherence
(>0.5) between LF or HF oscillations of RR interval and
SAP variabilities was required to calculate
22 ; and (2) the slope of the regression line,
obtained by least-squares regression
analysis,24 correlating changes of
systolic and diastolic BP induced pharmacologically
with corresponding changes of respective RR interval and MSNA at
rest.25 The values calculated in every subject
for each different dose of sodium nitroprusside and
phenylephrine were used as the points for individual
regression analysis. The mean slope of each group was obtained
by averaging the individual slopes.25
Data are expressed as mean±SEM. Differences between patients and control subjects were assessed by means of 1-way ANOVA. Student's t test for paired observations was used whenever appropriate. Differences were considered significant at values of P<0.05.
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Results |
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Basal Hemodynamic and Neurohumoral Data
With the patient supine, we recorded higher HR and MSNA values in COI patients than in control subjects; an example is shown in Figure 1
. Conversely, systemic BP, respiratory
frequency, and CVP were similar in both groups (Table 2). In addition to increased MSNA in COI
patients, plasma norepinephrine was higher
(P<0.05), whereas epinephrine levels were similar
to those of control subjects (Table 3).
In COI, the spectral marker of vagal SA node modulation
HFRR (NU) was reduced and LF/HF was higher than
in control subjects (Table 3). Likewise, LFSAP
was greater in the group of COI patients.
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Hemodynamic and Neurohumoral Response to
Tilt
In response to upright tilt, HR increased in both groups,
reaching, however, higher absolute values in COI patients (Figure 2 and Table 2
). Blood pressure remained
unchanged (although more oscillations were present in
the patients), and CVP was reduced to the same extent in both groups
(control subjects, -9.8±0.9 mm Hg; COI patients,
-7.5±1.2 mm Hg). Compared with the recumbent position,
respiratory frequency tended to increase in COI patients, whereas it
remained unchanged in control subjects.
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The indices of sympathetic function (MSNA, epinephrine and
norepinephrine levels, and LF/HF) increased during tilt
compared with supine, with higher values of norepinephrine
and LF/HF in COI patients (Table 3). Maximal changes in MSNA in
response to tilt were 14.9±2.3 bursts per minute in control subjects
and 9.12±1.74 bursts per minute in COI patients (P<0.05).
The maximal increase of LF/HF in control subjects and COI was 8.1±6.5
and 27.1±6.5, respectively. Note that MSNA increased by a larger
extent in control subjects than in COI patients; conversely, the
increase of LF/HF was higher in the COI group (Figure 3).
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Baroreflex Function
While subjects were supine, the index was similar
(P<0.06) in COI (18.6±3.1 ms/mm Hg) and in control
subjects (29.6±4.7 ms/mm Hg) (Figure 4). Analogous results were obtained when
baroreceptor reflex function was determined with drug infusions.
Indeed, the mean of the slopes of the regression lines relating SAP
changes and corresponding RR interval modifications was similar
(P<0.08) in COI (10.47±1.62 ms/mm Hg) and in control
subjects (15.69±2.4 ms/mm Hg). Furthermore, the gain of baroreceptor
modulation of MSNA was not different (P<0.44) in the 2
groups (COI, -0.98±0.2 and control subjects, -0.71±0.29 bursts per
minute per mm Hg).
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During the orthostatic stimulus (Figure 4), decreased
significantly in both groups, reaching lower values
(P<0.05) in patients affected by COI (2.6±0.4 ms/mm Hg)
than in control subjects (6.5±1.2 ms/mm Hg).
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Discussion |
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The main findings of our study include (1) an increased sympathetic outflow to the heart and to the vessels in COI patients compared with control subjects while supine; (2) during orthostatic stress in COI subjects, a blunted increase in MSNA associated with an enhancement of HR and of the spectral index LF/HF compared with control subjects; and (3) similar arterial baroreflex control of HR and MSNA in both groups.
Autonomic Control
In patients with COI, we observed unique alterations of autonomic
control of the cardiovascular system. These changes are
already present with the patient in the recumbent position, even
though many of these patients were almost completely
asymptomatic at rest. Indeed, MSNA and
LFSAP were higher than in control subjects,
indicating an increased sympathetic drive to blood vessels. In
addition, mean HR and LF/HF were greater in COI patients than in the
reference group, suggesting a shift of the sympathovagal modulation of
the SA node activity toward sympathetic predominance. These
observations are compatible with the presence of a hyperadrenergic
condition.
During tilt, an increase in MSNA in both groups was observed. However, the degree of change in MSNA in COI patients was lower than that of control subjects. This might reflect the fact that an increased sympathetic discharge at rest could inversely influence the capability of MSNA to increase further in response to the orthostatic stimulus, as described for stressors such as lower-body negative pressure and for the cold pressor test.26 However, in the COI group, the blunted increase in the sympathetic efferent discharge during tilt was associated with a more pronounced enhancement of HR and of LF/HF index compared with control subjects. This pattern suggests that the capability of increasing sympathetic outflow to the heart was not affected by the preexisting heightened cardiac sympathetic tone at rest. Therefore, the autonomic profile of COI patients seems to be characterized during the upright position by a reduced capacity to further increase sympathetic drive to the vascular tree in the lower extremities combined with a preserved or even increased capacity of activating the cardiac sympathetic modulation and withdrawal of the vagal activity to the SA node. The importance of the reduction of the vagal-related oscillations of HFRR during tilt may account for the discrepancy between the trends of LFNU and LF/HF. In fact, the increase of LF/HF can be largely ascribed to the reduction of the HF component of RR variability, whereas LFNU increased only slightly compared with control subjects.
Different mechanisms have been considered to account for the symptoms and the hemodynamic profile of COI patients.2 27 28 29 30 These included (1) the presence of a mild form of autonomic neuropathy,1 5 9 11 (2) the development of a hyperadrenergic state resulting from changes in circulating volume,7 8 or (3) sympathetic dysfunction emanating from the central nervous system.3 10 The blunted increase in MSNA combined with normal or increased sympathetic response to other regions (eg, cardiac) may be compatible with functional autonomic dysautonomia in the lower extremities. Although in absolute values, the increase in MSNA was similar in control subjects and in patients, the relative change is abnormal, considering that both groups had similar decreases in CVP. In keeping with this possibility, some studies have documented abnormal postganglionic sympathetic sudomotor function1 9 11 and reduced norepinephrine spillover in the lower extremities of selected patients suffering orthostatic intolerance at rest, after pharmacological stimulation, and after the cold pressor test.31 These observations alone, however, do not account for the increased sympathetic tone at baseline recorded in the present study and for many of the clinical findings reported in this syndrome (see below).
Alternatively, it can be argued that the increased sympathetic activity found in these patients may be the result of a compensatory mechanism secondary to venous pooling or a reduced plasma volume. However, the findings of increased HR, MSNA, LF/HF, and LFSAP at rest in the subset of patients characterized in our study argues, like the previous point, against this possibility. In addition, CVP, a parameter that in the presence of normal heart function is largely affected by central volume changes,32 33 was similar in the recumbent position and decreased by the same extent during tilt in both COI and control subjects. These observations challenge the hypothesis that the hyperadrenergic state observed in patients with COI might be solely a compensatory response to a reduced plasma volume or excessive venous pooling.
In light of these considerations, we believe that our findings are compatible with the presence of a central nervous system abnormality leading to a hyperadrenergic state.3 A strong indication is the finding of pronounced increments in resting supine plasma norepinephrine, MSNA, LF/HF, and LFSAP in patients with COI. The overall increase in resting sympathetic tone is striking because it is detected even in the absence of discernible orthostatic stress. Furthermore, a central alteration of sympathetic tone is compatible with the marked BP oscillations, the pronounced tachycardia, and the changes in regional sympathetic tone during orthostatic stress found in this study and with some of the clinical features (increased anxiety,28 response to stress,10 severe migraine-like headaches,3 and response to some central therapeutic agents such as clonidine34 and phenobarbital35 ) reported by others. It is also possible that some of the dissimilar findings reported in several studies (hypertension3 versus hypotension,8 11 elevated supine plasma norepinephrine and MSNA versus normal catecholamines and low norepinephrine spillover,31 therapeutic response to clonidine34 or barbiturates35 versus volume load or sympathomimetic agents36 ) can be explained by the inclusion of heterogeneous groups of patients in whom a different mechanism (or a combination of several) results in similar clinical symptoms.
In this study, we evaluated sympathetic tone by 3 different complementary methods that included microneurography, plasma catecholamines, and spectral analysis of HR and BP variabilities. During tilt, plasma norepinephrine levels were markedly higher in the group of patients with COI compared with control subjects, a finding that seems to be a hallmark of orthostatic intolerance.1 9 30 However, it must be noted that the observed enhancement of plasma norepinephrine levels in COI patients may not represent, per se, an increase in central sympathetic activity. For instance, standing induces changes in blood flow redistribution, which might have reduced norepinephrine clearance, as described in other conditions.37 Conversely, the increased MSNA and LF/HF ratio indicate, at least while the patient is supine, significant enhancement of sympathetic tone compatible with a hyperadrenergic state. These observations are consistent with data of a recent investigation by Novak et al,38 who also found evidence of a hyperadrenergic state in COI patients.
In general, different hemodynamic and sympathoneural responses are evident in subjects suffering from vasovagal syncope compared with COI patients. In vasovagal subjects, we25 and others39 40 have described a blunted increase in sympathetic activity during tilt, followed by progressive decrease and total disappearance before syncope. Not surprisingly, in vasovagal subjects, the postural loss of consciousness was preceded by a constant reduction in BP, with a "blunted" increase in HR.25 This contrasts with the results obtained in COI patients, in whom BP remained unchanged and HR dramatically increased during tilt. The different hemodynamic and sympathoneural profiles have important clinical implications, because COI patients often are confused with vasovagal patients, which then may result in inappropriate therapy.
Baroreflex Function
In the recumbent position, COI patients and control subjects
had similar baroreflex function. Therefore, the increased values of HR
and MSNA observed in COI patients at rest cannot be ascribed to an
impairment of the inhibitory modulation elicited by
arterial baroreceptor activity. Also, the index was
unchanged in the 2 groups at rest. During the tilt maneuver,
decreased in both control subjects and COI patients, reaching lower
values in the latter group. This observation suggests that in this
syndrome, baroreflex mechanisms still maintain their functional
integrity. Finally, the reduced values of observed during tilt in
COI patients primarily reflect the important reduction of total RR
variability and, consequently, of its spectral components as a result
of the enhancement of cardiac sympathetic modulation and of vagal
withdrawal.
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Conclusions |
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We conclude that in a subset of patients with COI, there is the presence of sympathetic dysfunction, which is characterized, in the recumbent position, by an augmented rate of firing of cardiac and blood vessel sympathetic fibers. During the assumption of the upright posture, an attenuated increase in the postganglionic sympathetic nerve discharge was found to be associated with a preserved, more pronounced shift of the cardiac sympathovagal modulation toward a sympathetic predominance in patients with COI compared with control subjects. This autonomic profile is associated with a preserved sensitivity of baroreflex mechanisms.
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Acknowledgments |
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We gratefully acknowledge the typing assistance of Isabella Ghirardelli, Varonica Watts, and Dorothea Boemer. Simona Piazza contributed to the analysis of baroreflex sensitivity data.
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Footnotes |
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Reprint requests to Rogelio Mosqueda-Garcia, MD, PhD, Division of Clinical Pharmacology, Dupont Pharmaceuticals Co, Chestnut Run Plaza, MR 2272, 974 Centre Rd, Wilmington, DE 19805.
Received May 4, 1998; revision received July 2, 1998; accepted July 21, 1998.
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Clin Sci. 1995;91:50–51.
-
Bernardi L, Salvucci F, Leuzzi S, Radaelli A, Calciati
A, Valle F, Savasta S, Scaramuzza A, Lorini R.
Cardiovascular reflex changes preceding episodes of
vasovagal syncope in pediatric subjects. Clin Sci. 1995;91:25–27.To evaluate possible postural alterations of
sympathetic function and of arterial baroreflex mechanisms,
16 patients with chronic orthostatic intolerance (COI) and
16 control subjects underwent invasive blood pressure, ECG, central
venous pressure, and muscle sympathetic nerve activity (MSNA)
recordings, both at rest and during a 75° tilt. Spectral
analysis of RR and systolic pressure variabilities was
performed. Baroreflex control of heart rate and MSNA was evaluated by
pharmacological probes. COI is characterized by an increase of
noradrenergic tone at rest and by a blunted
postganglionic muscle sympathetic response with cardiac sympathetic
overactivity during tilt. The functional responsiveness of baroreceptor
mechanisms is preserved.
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