(Circulation. 1997;96:575-580.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Volume Loading and Pressor Agents in Idiopathic Orthostatic Tachycardia
From the Clinical Research Center, Departments of Medicine (G.J., J.R.S., B.B., I.B., R.M.-G., R.M.R., D.R.), Pharmacology (G.J., J.R.S., I.B., R.M.-G., R.M.R., D.R.), and Neurology (D.R.), Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to David Robertson, MD, Clinical Research Center, AA3228 MCN, Vanderbilt University, Nashville, TN 37232-2195. E-mail david.robertson{at}mcmail.vanderbilt.edu
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Abstract |
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Background Idiopathic orthostatic tachycardia (IOT) is characterized by an increase in heart rate (HR) with standing of
30 bpm that is associated with elevated
catecholamine levels and orthostatic symptoms.
A dynamic orthostatic hypovolemia and
1-adrenoreceptor hypersensitivity have
been demonstrated in IOT patients. There is evidence of an autonomic
neuropathy affecting the lower-extremity blood vessels.
Methods and Results We studied the effects of
placebo, the 1-adrenoreceptor agonist
midodrine (5 to 10 mg), the
2-adrenoreceptor agonist clonidine (0.1
mg), and IV saline (1 L) in 13 patients with IOT. Supine and upright
blood pressure (BP) and HR were measured before and at 1 and 2 hours
after intervention. Midodrine decreased both supine and upright HR (all
HR values are given as bpm) at 2 hours (from 78±2 supine to 108±5
upright before treatment and from 69±2 supine to 95±5 upright after
treatment, P<.005 for supine and P<.01 for
upright). Saline decreased both supine and upright HR (from 80±3
supine to 112±5 upright before infusion and from 77±3 supine to 91±3
upright 1 hour after infusion, P<.005 for supine and
P<.001 for upright). Clonidine decreased supine HR (from
78±2 to 74±2, P<.03) but did not affect the HR increase
with standing. Clonidine very significantly decreased supine
systolic BP (from 109±3 at baseline to 99±2 mm Hg at 2
hours, P<.001), and midodrine decreased supine
systolic BP mildly.
Conclusions IOT responds best acutely to saline
infusion to correct the underlying hypovolemia. Chronically, this can
be accomplished with increased salt and water intake in conjunction
with fludrocortisone. The response of patients to the
1-agonist midodrine supports the hypothesis of partial
dysautonomia and indicates that the use of 1-agonists to
pharmacologically replace lower-extremity postganglionic sympathetics
is an appropriate overall goal of therapy. These findings are
consistent with our hypothesis that the tachycardia
and elevated catecholamine levels associated with IOT are
principally due to hypovolemia and loss of adequate lower-extremity
vascular tone.
Key Words: tachycardia • syncope • blood volume • blood pressure • catecholamines
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Idiopathic orthostatic tachycardia is but one of the manifestations of the more general disorder of orthostatic intolerance that has been described by many other names over the years (Table 1
). The syndrome tends to affect younger adults,
women more frequently than men. It is characterized by a dramatic
increase in HR with standing that is associated with a variety of
orthostatic symptoms that may include lightheadedness,
clouding of thought, blurring or dimming of vision, anxiety, shoulder
and neck pain, nausea, diaphoresis, and, occasionally, frank
syncope.
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The pathophysiology of the disorder is poorly characterized.
Patients frequently have elevated levels of catecholamines
with standing, which has encouraged the view that the disorder is a
primary "hyperadrenergic state."1 On the other hand,
patients also have baseline absolute hypovolemia,2 3
excessive pooling of blood in the lower extremities with standing, and
an exaggerated orthostatic hypovolemia4 as
well as evidence of lower-extremity sympathetic
denervation5 6 7 associated with
-adrenoreceptor hypersensitivity to local infusion
of NE5 and systemic infusion of
phenylephrine.7 These findings are
consistent with denervation of blood vessels in the lower
extremities, in which case, high levels of circulating
catecholamines would be secondary.
Perhaps because of these confusing and sometimes contradictory findings, effective treatment has been lacking. Several anecdotal cases indicate that patients improve with lower-extremity compression,5 sodium loading,8 fludrocortisone,6 and ß-blockade.1 To date, however, there have been no controlled studies to evaluate the effectiveness of any intervention on the orthostatic tachycardia. We hypothesized that if the orthostatic tachycardia in orthostatic intolerance were due to a primary hyperadrenergic state, then it should respond to blunting of excessive central sympathetic outflow (eg, clonidine). However, if the orthostatic tachycardia were due to a defect in peripheral sympathetic nerve function, then the orthostatic tachycardia should respond to correction of the underlying hypovolemia and to pharmacological augmentation of constriction in lower-extremity blood vessels (eg, midodrine).
Therefore, we evaluated the effectiveness of volume loading, the
direct-acting 1-adrenergic agonist midodrine, and the
2-adrenergic agonist clonidine on
orthostatic BP and HR.
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Methods |
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The study group consisted of 13 patients with IOT (11 women and 2 men) aged 18 to 47 (mean, 33±3) years who were referred to the Autonomic Dysfunction Center at Vanderbilt University Medical Center between October 1994 and January 1996 for evaluation and treatment of debilitating symptoms consistent with orthostatic intolerance. Patients were enrolled in the study if they met the following criteria: (1) upright HR increase >30 bpm with <20/10 mm Hg decrease in BP (ie, without orthostatic hypotension as defined by the criteria of the American Autonomic Society9 ) within 5 minutes of standing on at least three separate occasions; (2) elevated plasma NE level (>600 pg/mL) with standing; and (3) daily incidence of at least five of the following, all associated with upright but not supine posture: fatigue, anxiety, dizziness, blurred vision, headache, clamminess, tremulousness, palpitations (defined as an awareness of heartbeat), chest discomfort, shortness of breath, nausea, and presyncope or, occasionally, frank syncope.
Subjects with systemic illnesses capable of affecting the autonomic nervous system (eg, diabetes mellitus, systemic lupus erythematosus, amyloidosis) were excluded. Thyroid dysfunction was ruled out by normal thyroid function tests, and when adrenal dysfunction was suspected on clinical grounds, adrenal function was evaluated with cortisol levels and the cosyntropin stimulation test. Renal function, liver function, and hematological screening were normal. No subject had a history of alcohol or drug abuse. Echocardiography had been done on all subjects to exclude anatomical abnormalities, and 24-hour Holter monitoring had been performed in all subjects on at least one occasion to exclude arrhythmias. Exercise treadmill testing had been done on several patients with specific complaints. Many patients had also had an MRI of the head; all results were normal. All investigational procedures were approved by the Institutional Review Board, and patients gave informed consent prior to the study.
Protocol
Subjects were admitted to the Elliot V. Newman Clinical Research
Center at Vanderbilt University and were placed on a low-monoamine,
caffeine-free diet containing 150 mEq/d sodium and 70 mEq/d potassium
for at least 3 days before testing. All medications had been
discontinued at least 2 weeks before admission. Patients were
interviewed by using a questionnaire to determine the type and extent
of clinical symptoms, medical history, and associated diagnoses. Plasma
catecholamine levels, BP, and HR were assessed overnight
supine and after 2.5 and 5 minutes of upright posture. Autonomic
function tests were performed,10 and Valsalva's maneuver,
respiratory arrhythmia, and respiratory ratio were used as
indices of cardiac parasympathetic activity.
Cardiovascular sympathetic activity was assessed by
evaluating the degree of hypotension induced by hyperventilation and
the degree of hypertension induced by the cold pressor test and by
sustained handgrip. These results were compared with those of 10 age-
and gender-matched control subjects; no significant differences between
the two groups in these variables were detected.
Blood samples for catecholamine and aldosterone
levels and plasma renin activity were collected in plastic syringes
from an indwelling catheter in a peripheral vein,
immediately transferred to chilled, evacuated heparinized tubes, and
placed on ice. Plasma was separated from cells by using refrigerated
centrifugation at -4°C and processed within 2 weeks.
For NE and EPI measurements, a 1-mL aliquot of plasma was partially
purified by batch alumina extraction followed by reverse-phase liquid
chromatography for separation. Components were then
quantified by using electrochemical detection with a modification of
the technique of Goldstein et al.11 Recovery through
alumina extraction is 
75% for both NE and EPI.
Catecholamine concentrations in each sample were corrected
for recovery of a known quantity of the internal standard
dihydroxybenzylamine, which was run simultaneously. The
limits of detection for NE and EPI are 5 to 15 pg/mL. Plasma renin
enzymatic activity was assessed by the rate of conversion of
angiotensinogen to angiotensin I and was
expressed as nanograms of angiotensin I produced per
milliliter of plasma per hour. Plasma aldosterone
concentration was determined by using a radioimmunoassay (Coat-a-Count,
Diagnostic Products Corp).
Medical Trials
All patients received one of three test medications on separate
days. Test medications included placebo, saline loading, clonidine (an
2-adrenergic agonist), and midodrine (an
1-adrenergic agonist without any central effect). The
dose of midodrine for each subject (5 to 10 mg) was determined based on
their previously determined sensitivity to -adrenergic agonism.
Saline (1 L) was infused by IMED pump over 1 hour. Supine BP and HR
were measured before and immediately after infusion.
Orthostatic BP and HR were then measured. The patient
resumed a seated position, and 0.1 mg clonidine PO was given.
Studies were conducted at least 2 hours after the last meal with the patient seated in bed with the legs horizontal. A heplock was placed at least 1 hour before the study for IV access. BP was measured by using an automated device (Dynamap) and confirmed by manual cuff measurement. Medication was taken by mouth with 50 mL water. At 1 and 2 hours after administration of the test medication, the patient's bed was lowered to horizontal for 10 minutes, and BP and HR were measured supine and then 3 minutes after standing. All drug trials were done under the supervision of a research nurse.
Statistical Analysis
Results are expressed as mean±SEM. Data were analyzed
with Quattro Pro (Borland International, Inc) and GraphPad Prism
(GraphPad Software Inc, version 2.0, October 1995). Paired and unpaired
t tests were used for comparisons between groups and within
one group before and after treatment. To compare between two treatment
groups, two-way ANOVA for repeated measurements was used. The criterion
for significance was P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Prominent clinical characteristics of the study group are depicted in Table 2
. Orthostatic lightheadedness,
dizziness, visual changes, palpitations, chest discomfort, shortness of
breath, nausea, fatigue, and exercise intolerance were the most common
complaints of patients. Thirty-nine percent of patients reported the
occurrence of syncope, but it usually occurred only with prolonged
standing, and patients had learned to prevent it by sitting or lying
down as symptoms built in intensity. Fatigue was common among patients
but only three met the Center for Disease Control criteria for chronic
fatigue syndrome. Forty-six percent of the patients had been diagnosed
with mitral valve prolapse, but evidence of myxomatous degeneration was
not found in any of them; no patient had significant mitral
regurgitation. Symptoms consistent with
irritable bowel syndrome were reported by 23% of the patients.
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The effect of supine and upright posture on HR, BP, and plasma
catecholamines on study and control subjects are shown in
Table 3. In patients, the mean increase in HR with
standing was 50 bpm compared with 18 bpm in normal volunteers. There
were no significant differences in orthostatic change in
SBP between patients and control subjects, but the upright DBP was
significantly (P=.04) greater in patients. Both supine and
upright NE and EPI levels were significantly greater in patients than
control subjects, which was expected given our study's inclusion
criteria.
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Results of Medical Trials
Fig 1 shows the effects of the test
medications on supine BP and HR. Supine HR did not change significantly
with placebo (76±3 before and 75±3 and 74±2 bpm at 1 and 2 hours,
respectively), but SBP decreased significantly after 2 hours (from
114±3 to 107±2 mm Hg, P<.004), and DBP decreased
significantly after 1 and 2 hours (from 69±2 to 66±2 to 63±2
mm Hg, P<.05 and P<.01 after 1 and 2 hours,
respectively). Immediately after infusion, saline decreased both HR
(from 80±2 to 77±2 bpm, P<.05) and SBP (from 114±4 to
109±3 mm Hg, P<.02) but did not change DBP.
Clonidine significantly decreased HR (from 79±2 to 75±2 bpm after 1
hour [P<.05] and 73±3 bpm after 2 hours
[P<.03]), SBP (from 114±4 to 105±2 mm Hg after 1
hour [P<.009] and 99±2 mm Hg after 2 hours
[P<.0009]), and DBP (from 64±2 to 57±2 mm Hg
after 2 hours [P<.004]). Midodrine was the most effective
intervention in decreasing supine HR (from 79±2 to
72±2 bpm after 1 hour [P<.005] and
69±2 bpm after 2 hours [P<.0007]) with only
minor BP changes (significant only for SBP 109±2 before to
105±2 mm Hg after 2 hours [P<.05]).
This change in SBP after 2 hours was not significantly different from
the change seen with placebo after 2 hours. When each treatment group
was compared with the placebo group, the change in DBP was significant
only for clonidine (P<.01). The change in SBP was
significant for clonidine (P<.05) and saline
(P<.05). The HR change was significant only for midodrine
(P<.05).
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Effects of trial medications on orthostatic changes in BP
and HR are illustrated in Fig 2. Placebo had no
significant effect on HR, SBP, or DBP. Saline infusion was most
effective in blunting the orthostatic
tachycardia in these patients (HR increase 32±5 before
infusion and 14±2 bpm after infusion, P<.001). Saline
infusion also caused an orthostatic increase in SBP (-5±3
before infusion and 6±2 mm Hg after infusion,
P<.002), but it had no effect on the
orthostatic change in DBP. Clonidine allowed a significant
drop in SBP with standing (2±1 before and -6±3 mm Hg after 2
hours, P<.03) but did not blunt orthostatic
changes in HR and DBP. In addition to decreasing supine HR, midodrine
also significantly blunted changes in HR with standing (30±5 before
and 25±4 bpm after 1 hour and 26±3 bpm after 2 hours,
P<.05 for both) but had no significant effect on
orthostatic changes in either SBP or DBP. Comparing each
treatment group with the placebo group, the most significant effect on
orthostatic changes was due to saline (SBP,
P<.01, and HR, P<.002).
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SBP, Informal assessment revealed that saline infusion improved symptoms of orthostasis most significantly, and most patients said it made them feel better than they had felt since the onset of their illness. Clonidine, on the contrary, universally made symptoms worse. In some patients, midodrine had minor well-known side effects, such as scalp tingling or itching and piloerection; our patients did not report these as being unpleasant. There was overall improvement in orthostatic symptoms with midodrine.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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IOT, characterized by orthostatic symptoms but not orthostatic hypotension in a setting of increased upright HR and increased upright plasma NE levels, has been very difficult to treat. There are probably many reasons for this. One is a mismatch between pathophysiology and therapy. With improved understanding of the ultimate causes of such illnesses, that mismatch can presumably be addressed. A second reason is that the beneficial properties of certain therapies may be counterbalanced by actions that worsen other aspects of the condition. For example, some of the most severely affected patients with hypovolemia may have attenuation of their HR in response to a ß-blocker, but the concomitant reduction in plasma renin activity could exacerbate the underlying volume deficit, thus compromising the orthostatic BP adjustment. A third reason that our pharmacotherapy may be inadequate is that our dosages may be inappropriate or insufficiently individualized. A final problem underlying almost all previous studies has been the heterogeneity of patients included in the study.
In this investigation, we applied stringent historical, hemodynamic, and neurohumoral criteria to create as homogeneous a group of study subjects as possible. It is noteworthy that this population had a greater incidence than would be expected of several clinical conditions. These included, in descending order of frequency, mitral valve prolapse, irritable bowel syndrome, chronic fatigue syndrome, and inflammatory bowel disease. One subject had fibromyalgia. It is noteworthy that almost half our subjects had auscultatory and/or echocardiographic evidence of mitral valve prolapse.
The orthostatic symptoms observed in our patients are similar to those reported by others,1 6 8 but in some cases, somewhat more frequent. This probably reflects the greater severity of illness in the patients in the present study compared with patients in previous studies. It is noteworthy that some orthostatic symptoms were prerequisites for inclusion into this study, a factor that would obviously have the effect of increasing the frequency of such symptoms. The most common symptoms of patients with upright posture were lightheadedness/dizziness, exercise intolerance, blurred vision, fatigue, and chest discomfort. Each of these occurred in more than half the individuals in our population.
The rationale for our study was to compare and contrast three
therapeutic modalities with fundamentally distinct mechanisms of
action. We compared normal saline, which raises plasma volume, with
midodrine, an 1-agonist prodrug that acts to
vasoconstrict the vasculature,12 13 and also with
clonidine, an 2-adrenoreceptor agonist
that acts centrally to reduce sympathetic outflow and enhance
parasympathetic activation.14 Our studies demonstrated
that expansion of the intravascular volume by infusion of 1 L normal
saline was an extremely effective (though very transient) means of
improving the orthostatic tachycardia and
orthostatic tolerance of our patient population. The likely
mechanism is through the loading of baroreceptors, which would result
in a reflexive lowering of sympathetic tone.
Midodrine at an average dose of 5 to 10 mg PO significantly reduced HR
with little effect on the systemic BP and the dosage employed.
Presumably, the reduction in HR with this agent is due to attenuated
baroreflex activation consequent to improved
cardiovascular variables that DBP and SBP
measurements are insufficiently sensitive to detect.15
There are several reasons the midodrine might exert such an effect.
Midodrine reduces muscle sympathetic nerve activity in normal control
subjects.15 Thus, it is possible that there is some
sympathetic denervation in our patients and that midodrine may
selectively compensate for that by stimulating denervated
1-adrenoreceptors. It is noteworthy that
we have demonstrated7 a twofold increase in BP sensitivity
to intravenous boluses of the 1-agonist
phenylephrine in patients similar to these. If there is a
patchy denervation in this disorder, the hypersensitivity may derive
from those areas of denervation, in which case low dosages of midodrine
may be especially vasoconstrictive in those denervated
sites. Whether this is truly the pathophysiology cannot easily be
ascertained.
The response to clonidine was disappointing. Though plasma NE was not measured after administration of the test medications, clonidine is known to decrease plasma NE.16 There was a fall in HR, but this favorable effect on HR with upright posture was counterbalanced by concomitant declines in SBP and DBP that were especially prominent 2 hours after the clonidine dose. Patients generally tolerated clonidine poorly.
The strength of our investigation is that it was conducted in a homogeneous population of subjects with clearly defined admission criteria. Furthermore, these subjects were studied in metabolic balance as inpatients on a metabolic ward. A limitation of our investigation is that it is a short-term rather than a long-term trial. Nevertheless, the present observations suggest that maneuvers that increase blood volume chronically could be of benefit in correcting the substantial (5% to 25%) hypovolemia we encounter in these patients. While administration of normal saline intravenously is impractical over the long term, the success of this therapy provides a strong rationale for the chronic use of salt tablets and fludrocortisone, two commonly used approaches in the management of these patients. Although fludrocortisone acutely raises plasma volume, it is still uncertain that this increased plasma volume is maintained.17 Other agents that may increase blood volume chronically include epoetin alfa,18 but this agent has not been proven to be effective long-term in these patients.19
In conclusion, in this carefully selected group of patients with
orthostatic intolerance characterized by raised HR on
standing and orthostatic symptoms but without significant
orthostatic hypotension, we found maneuvers that increase
blood volume (physiological saline) and stimulate
1-adrenoreceptors (midodrine) to be
superior to clonidine in an acute setting. Our data suggest that
clonidine should be reserved for those subjects who have significant
hypertension in addition to their orthostatic intolerance.
Long-term studies with the 1-agonist prodrug midodrine,
administered at modest doses, need to be undertaken to demonstrate
preservation of beneficial effect and long-term tolerability.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants RR00095 and NS33460 and National Aeronautics and Space Administration grants NAG9-563 and NAGW 3873. Dr Jacob is the recipient of a Merck International Fellowship in clinical pharmacology.
Received June 17, 1996; revision received January 31, 1997; accepted February 5, 1997.
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J. M. Stewart, J. Munoz, and A. Weldon Clinical and Physiological Effects of an Acute {alpha}-1 Adrenergic Agonist and a {beta}-1 Adrenergic Antagonist in Chronic Orthostatic Intolerance Circulation, December 3, 2002; 106(23): 2946 - 2954. [Abstract] [Full Text] [PDF]
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C. Schroeder, V. E. Bush, L. J. Norcliffe, F. C. Luft, J. Tank, J. Jordan, and R. Hainsworth Water Drinking Acutely Improves Orthostatic Tolerance in Healthy Subjects Circulation, November 26, 2002; 106(22): 2806 - 2811. [Abstract] [Full Text] [PDF]
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C. Schroeder, J. Tank, M. Boschmann, A. Diedrich, A. M. Sharma, I. Biaggioni, F. C. Luft, and J. Jordan Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance Circulation, January 22, 2002; 105(3): 347 - 353. [Abstract] [Full Text] [PDF]
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A. G. Hermosillo, K. Jauregui-Renaud, A. Kostine, M. F. Marquez, J. L. Lara, and M. Cardenas Comparative study of cerebral blood flow between postural tachycardia and neurocardiogenic syncope, during head-up tilt test Europace, January 1, 2002; 4(4): 369 - 374. [Abstract] [PDF]
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J. Jordan, J. R. Shannon, A. Diedrich, B. K. Black, and D. Robertson Increased Sympathetic Activation in Idiopathic Orthostatic Intolerance: Role of Systemic Adrenoreceptor Sensitivity Hypertension, January 1, 2002; 39(1): 173 - 178. [Abstract] [Full Text] [PDF]
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R. Furlan, G. Jacob, L. Palazzolo, A. Rimoldi, A. Diedrich, P. A. Harris, A. Porta, A. Malliani, R. Mosqueda-Garcia, and D. Robertson Sequential Modulation of Cardiac Autonomic Control Induced by Cardiopulmonary and Arterial Baroreflex Mechanisms Circulation, December 11, 2001; 104(24): 2932 - 2937. [Abstract] [Full Text] [PDF]
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W. B. Farquhar, J. A. Taylor, S. E. Darling, K. P. Chase, and R. Freeman Abnormal Baroreflex Responses in Patients With Idiopathic Orthostatic Intolerance Circulation, December 19, 2000; 102(25): 3086 - 3091. [Abstract] [Full Text] [PDF]
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 G. Jacob, F. Costa, J. R. Shannon, R. M. Robertson, M. Wathen, M. Stein, I. Biaggioni, A. Ertl, B. Black, and D. Robertson The Neuropathic Postural Tachycardia Syndrome N. Engl. J. Med., October 5, 2000; 343(14): 1008 - 1014. [Abstract] [Full Text] [PDF]
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J. M. Stewart and A. Weldon Vascular perturbations in the chronic orthostatic intolerance of the postural orthostatic tachycardia syndrome J Appl Physiol, October 1, 2000; 89(4): 1505 - 1512. [Abstract] [Full Text] [PDF]
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 H. Izzedine, R. Azar, K. Zahiri, J. Rottembourg, and G. Deray Haematological toxicity of midodrine in haemodialysis patients Nephrol. Dial. Transplant., October 1, 2000; 15(10): 1715 - 1716. [Full Text] [PDF]
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R. E. Shapiro, B. Winters, M. Hales, T. Barnett, D. A. Schwinn, N. Flavahan, and D. E. Berkowitz Endogenous Circulating Sympatholytic Factor in Orthostatic Intolerance Hypertension, October 1, 2000; 36(4): 553 - 560. [Abstract] [Full Text] [PDF]
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J. R. Shannon, N. L. Flattem, J. Jordan, G. Jacob, B. K. Black, I. Biaggioni, R. D. Blakely, and D. Robertson Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency N. Engl. J. Med., February 24, 2000; 342(8): 541 - 549. [Abstract] [Full Text] [PDF]
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G. Jacob, J. R. Shannon, F. Costa, R. Furlan, I. Biaggioni, R. Mosqueda-Garcia, R. M. Robertson, and D. Robertson Abnormal Norepinephrine Clearance and Adrenergic Receptor Sensitivity in Idiopathic Orthostatic Intolerance Circulation, April 6, 1999; 99(13): 1706 - 1712. [Abstract] [Full Text] [PDF]
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K. Narkiewicz and V. K. Somers Chronic Orthostatic Intolerance : Part of a Spectrum of Dysfunction in Orthostatic Cardiovascular Homeostasis? Circulation, November 17, 1998; 98(20): 2105 - 2107. [Full Text] [PDF]
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R. Furlan, G. Jacob, M. Snell, D. Robertson, A. Porta, P. Harris, and R. Mosqueda-Garcia Chronic Orthostatic Intolerance : A Disorder With Discordant Cardiac and Vascular Sympathetic Control Circulation, November 17, 1998; 98(20): 2154 - 2159. [Abstract] [Full Text] [PDF]
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J. Jordan, J. R. Shannon, B. K. Black, S. Y. Paranjape, J. Barwise, and D. Robertson Raised Cerebrovascular Resistance in Idiopathic Orthostatic Intolerance : Evidence for Sympathetic Vasoconstriction Hypertension, October 1, 1998; 32(4): 699 - 704. [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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