Cardiac Sympathetic Dysautonomia in Chronic Orthostatic Intolerance Syndromes
Background— In postural tachycardia syndrome (POTS) and repeated neurocardiogenic presyncope (NCS), orthostatic intolerance occurs without persistent sympathetic neurocirculatory failure. Whether these conditions involve abnormal cardiac sympathetic innervation or function has been unclear.
Methods and Results— Patients with POTS or NCS underwent measurements of neurochemical indices of cardiac release, reuptake, and synthesis of the sympathetic neurotransmitter norepinephrine based on entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover), cardiac extraction of circulating 3H-norepinephrine, and cardiac production of dihydroxyphenylalanine and measurement of left ventricular myocardial innervation density using 6-[18F]fluorodopamine positron emission tomographic scanning. Mean cardiac norepinephrine spillover in POTS (171±30 pmol/min, N=16) was higher and in NCS (62±9 pmol/min, N=20) was lower than in a large group of healthy volunteers (102±9 pmol/min, N=52) and in a subgroup of age-matched healthy women (106±18 pmol/min, N=11). Both patient groups had normal cardiac extraction of 3H-norepinephrine, normal cardiac production of dihydroxyphenylalanine, and normal myocardial 6-[18F]fluorodopamine-derived radioactivity.
Conclusions— POTS and NCS differ in tonic cardiac sympathetic function, with increased cardiac norepinephrine release in the former and decreased release in the latter. Both groups had normal values for indices of function of the cell membrane norepinephrine transporter, norepinephrine synthesis, and density of myocardial sympathetic innervation. Because POTS and NCS both include specific abnormalities of cardiac sympathetic function, both can be considered forms of dysautonomia.
Received June 17, 2002; revision received August 16, 2002; accepted August 16, 2002.
In orthostatic intolerance, prolonged standing produces lightheadedness, dizziness, faintness, or syncope. Deficient reflexive sympathetic neurocirculatory regulation explains orthostatic intolerance in chronic autonomic failure; however, most patients with persistent orthostatic intolerance do not have sympathetic neurocirculatory failure. After internal medical, cardiological, neurological, and endocrinologic evaluation has excluded identifiable causes, such as blood volume depletion, arrhythmias, seizures, and adrenal insufficiency, the pathophysiological mechanism of chronic orthostatic intolerance usually remains obscure.
Various names have been used for the combination of tachycardia during standing (≥110 bpm) or excessive orthostatic increases in pulse rate (≥30 bpm), orthostatic symptoms suggesting catecholamine effects, and absence of orthostatic hypotension. In this study we defined this pattern as postural tachycardia syndrome (POTS).
Patients with repeated neurocardiogenic syncope or presyncope (NCS) often also have chronic orthostatic intolerance between episodes, without orthostatic tachycardia.1 The clinical picture can overlap that in chronic fatigue syndrome.2 The frequency of actual syncope depends on the individual patient’s recognition of warning symptoms and avoidance of precipitating factors. In this study, we defined recurrent presyncope as a chronically repeated, consistently elicited sensation of lightheadedness or faintness, where the patient feels that loss of consciousness would surely ensue without rapid compensatory adjustments.
Conversely, patients with chronic fatigue syndrome often complain of orthostatic intolerance, and tilt-table testing evokes neurally mediated hypotension and syncope or excessive tachycardia, or both, in a substantial proportion of patients.3–6⇓⇓⇓
Neuronal reuptake of norepinephrine via the cell membrane norepinephrine transporter (uptake-1) is the main means of inactivation of norepinephrine in the heart7 and a key factor in regulation of delivery of norepinephrine to myocardial adrenoceptors. Affected members of a kindred with POTS have a hypofunctional mutation of this transporter.8 To date, however, no study has tested whether decreased function of the cell membrane norepinephrine transporter characterizes the much more common sporadic form of this syndrome. Results of power spectral analysis of heart rate variability have been taken to suggest increased cardiac sympathetic tone or an excess of sympathetic over vagal tone (sympathovagal imbalance).9 Such a physiological index cannot examine important determinants of cardiac sympathoneural function, including exocytotic release of norepinephrine from cardiac sympathetic terminals, norepinephrine synthesis, the density of sympathetic innervation, and in particular uptake-1 activity.
Although evoked episodes in patients with NCS are associated with decreased sympathetic outflow to skeletal muscle and increased plasma epinephrine levels, which might help explain the characteristic skeletal muscle vasodilation,10 studies of overall autonomic function between episodes have also so far not revealed consistent, specific abnormalities. During supine rest, plasma levels of norepinephrine, rates of peroneal sympathetic nerve traffic, and power spectra of heart rate variability are normal.11–14⇓⇓⇓ As in POTS, in NCS relatively little is known about tonic cardiac sympathetic innervation and function.
In this study we examined cardiac sympathetic innervation and function in chronic orthostatic intolerance syndromes, addressing the following questions. First, does POTS or NCS involve altered cardiac release, neuronal uptake, or synthesis of norepinephrine or abnormal density of sympathetic innervation in the left ventricular myocardium? Second, if so, does heart rate relate to any of these abnormalities? Third, does pharmacologic stimulation of norepinephrine release from cardiac sympathetic terminals reveal altered presynaptic modulation of norepinephrine release or altered cardiac uptake-1 activity in these conditions? Fourth, does POTS differ from NCS in plasma levels of catecholamines during supine rest or orthostasis?
To answer these questions, we measured the rates of entry of norepinephrine into coronary sinus plasma (cardiac norepinephrine spillover)15 and cardiac extraction of 3H-norepinephrine and production of dihydroxyphenylglycol and dihydroxyphenylalanine16 at baseline, during exposure to mild lower-body negative pressure (LBNP), and during intravenous infusion of the α2 adrenoceptor blocker yohimbine.17 The same patients had thoracic positron emission tomographic scanning after intravenous injection of the sympathoneural imaging agent 6-[18F]fluorodopamine to evaluate cardiac sympathetic innervation.18
The study protocol was approved by the Intramural Research Board of the National Institute of Neurological Disorders and Stroke. Patients gave informed written consent before participating.
The subjects included 36 patients with POTS and 36 with NCS referred for autonomic function testing (Table 1). All patients had orthostatic intolerance (dizziness, lightheadedness, syncope, or presyncope during standing) or a previously documented positive tilt-table test (excessive orthostatic tachycardia, neurally mediated hypotension, or neurally mediated syncope). None had orthostatic hypotension, defined by a fall in systolic blood pressure of 20 mm Hg or more after 5 minutes of standing up from lying supine during the intake physical examination, and none had sympathetic neurocirculatory failure, detected by abnormal responses of beat to beat blood pressure during the Valsalva maneuver.19
Of the 72 patients, 36 (16 with POTS and 20 with NCS) underwent right heart catheterization for measurements of cardiac norepinephrine spillover and 40 (18 with POTS and 22 with NCS) underwent cardiac sympathoneural imaging by 6-[18F]fluorodopamine scanning. Thirty-four patients (14 with POTS and 20 with NCS) underwent both procedures.
Control data from right heart catheterization were obtained from a database of 52 healthy volunteers, including a subgroup of 11 healthy women (mean age, 35 years; 7 at the Baker Medical Research Institute and 4 at the NIH). Control data for effects of yohimbine infusion were obtained from 8 patients referred for chest pain and normal coronary arteries. For 6-[18F]fluorodopamine scanning results, normal control data were obtained from 26 healthy volunteers (mean age, 37 years). For mean arterial pressure and heart rate during supine rest, values were retrieved from a database of untreated healthy volunteers studied by our group during similar invasive procedures.
Patients could continue treatment with a serotonin reuptake blocker or fludrocortisone but tapered and stopped adrenoceptor-active drugs and any tricyclics before admission.
After placement of a brachial arterial catheter, arm venous catheters, and a right internal jugular venous catheter advanced into the coronary sinus, 3H-norepinephrine (levo-2,5,6-3H-norepinephrine, New England Nuclear) was infused intravenously. Coronary sinus blood flow was measured by thermodilution and arterial and great cardiac venous or coronary sinus blood sampled after at least 20 minutes of 3H-norepinephrine infusion.
For positron emission tomographic scanning, the subject’s thorax was positioned in a GE Advance (General Electric) scanner. 6-[18F]fluorodopamine (specific activity, 0.2 to 1.0 Ci/mmol, dose usually 1.0 mCi) was infused intravenously over 3 minutes, with emission scanning for up to 3 hours. For plasma 6-[18F]fluorodopamine measurements, arterial blood was sampled via an indwelling brachial arterial catheter.
To release endogenous norepinephrine from cardiac sympathetic nerves, yohimbine was given intravenously as a 3-minute bolus (0.125 mg/kg) followed by a constant infusion (1 μg/kg per min) for 12 minutes. LBNP was delivered using a sealed barrel at −15 cm water for a minimum of 15 minutes. Arterial and great cardiac venous or coronary sinus plasma was assayed for endogenous and 3H-labeled catechols by previously validated methods.20,21⇓
Cardiac norepinephrine spillover was quantified from the arterial and cardiac venous concentrations of total and 3H-norepinephrine and coronary sinus plasma flow. In patients who underwent great cardiac vein rather than coronary sinus sampling, coronary sinus blood flow was estimated from the ratio (2.16) of coronary sinus to great cardiac vein blood flow in other subjects (N=28).
To analyze 6-[18F]fluorodopamine scanning images, circular regions of interest (diameters approximately one half the ventricular wall width) were created using time-averaged (5- to 180-minute) frames of single slices. Radioactivity concentrations in 2 regions each in the left ventricular free wall and septum were averaged. Tomographic data were divided into 5- to 30-minute intervals. Decay-corrected concentrations were adjusted for the dose of radioactive drug per kilogram of body weight and expressed in units of nCi · kg/cc · mCi.
Differences between the patient groups in clinical findings, hemodynamics, norepinephrine spillovers, and plasma catechols were assessed by independent-means t tests, linear regression, and χ2 tests as appropriate (StatViewSE+Graphics, Abacus Concepts).
6-[18F]fluorodopamine-derived radioactivity in the interval from 5 to 10 minutes after initiation of the 3-minute infusion of 6-[18F]fluorodopamine was used for statistical tests involving a single data point per subject. Values were expressed as mean±SEM.
POTS and NCS occurred mainly in relatively young adult women (Table 1). Patients with either condition usually had multiple other symptoms besides orthostatic intolerance, the most common the same in the two groups—chronic fatigue, presyncope, disability, syncope, chest pain, heat intolerance, and headache. The groups differed predictably in terms of several parameters, such as the frequencies of syncope, presyncope, orthostatic intolerance, syncope during tilt-table testing, and excessive tachycardia during tilt-table testing. Patients with POTS more frequently noted benefit from treatment with fludrocortisone. The groups did not differ in reported benefit from other treatments or in the frequencies of chronic fatigue, disability, headache, heat intolerance, or chest pain.
During supine rest, the group with POTS had a higher mean heart rate and tended to have higher mean arterial pressure than did the group with NCS (Table 2). Neither group differed from the control group with chest pain or the age- and sex-matched healthy volunteers in coronary sinus blood flow (Table 2). Patients with POTS seemed to have relative tachycardia even during supine rest, based on differences in mean values from healthy volunteers.
Cardiac Norepinephrine Spillover
One patient with POTS had hypofunctional mutation of the cell membrane norepinephrine transporter; all neurochemical data from this patient were excluded.
Cardiac norepinephrine spillover in POTS averaged more and in NCS less than in healthy volunteers as a whole (Figure 1) or in age- and sex-matched volunteers (Table 2). The POTS group had significantly higher and the NCS group a tendency (P=0.09) toward lower cardiac norepinephrine spillover than did the control group with chest pain with normal coronary arteries (95±22 pmol/min).
Individual values for heart rate correlated positively with those for cardiac norepinephrine spillover in POTS and NCS (r=0.54, P=0.001; Figure 2) and across all subject groups (chronic orthostatic intolerance, chest pain with normal coronary arteries, healthy volunteers, r=0.45, P=0.0001).
Yohimbine augmented cardiac norepinephrine spillover more in POTS than in NCS or chest pain (Figure 3). During yohimbine infusion, cardiac norepinephrine spillover in POTS averaged about 5 times that in NCS (t=2.69, P=0.01) and was significantly higher than in the group with chest pain and normal coronary arteries. In POTS or NCS, the proportionate increment in heart rate during yohimbine infusion correlated significantly positively with that in cardiac norepinephrine spillover (r=0.59 and r=0.50); the absolute increment in heart rate correlated significantly positively with the log of the absolute increment in cardiac norepinephrine spillover (r=0.44 and r=0.60).
During supine rest, cardiac extraction of 3H-norepinephrine was normal in both POTS and NCS (Figure 3). All patients with POTS or NCS had easily detected myocardial 6-[18F]fluorodopamine-derived radioactivity. Myocardial 6-[18F]fluorodopamine-derived radioactivity was higher in both groups than in healthy subjects (Figure 3). During administration of 6-[18F]fluorodopamine, both patient groups also had higher concentrations of 6-[18F]fluorodopamine in arterial plasma than the age-matched healthy volunteers. After adjustment for the time-integrated arterial plasma 6-[18F]fluorodopamine concentration, time-activity curves for myocardial 6-[18F]fluorodopamine-derived radioactivity in the POTS and NCS did not differ from that in the age-matched healthy volunteers (data not shown).
During yohimbine infusion, the absolute increment in arterial dihydroxyphenylglycol, expressed as a ratio of the absolute increment in arterial norepinephrine, was normal in POTS and NCS (Figure 3). Across all subjects the ratio of dihydroxyphenylglycol to norepinephrine in arterial plasma decreased substantially from baseline (Table 3, F=115, P=0.0001), without a significant group difference in the extent of decrease. Cardiac dihydroxyphenylglycol spillover changed relatively little (Table 3), whereas cardiac norepinephrine spillover increased substantially in all 3 patient groups.
Cardiac extraction of 3H-norepinephrine decreased during yohimbine infusion, by 18±5% in POTS, 10±3% in NCS, and 6±2% in controls. The extraction fraction varied negatively with the log of cardiac norepinephrine spillover (r=−0.65, P=0.0001, Figure 2). For a given rate of cardiac norepinephrine spillover, the cardiac extraction fraction of norepinephrine was normal in patients with POTS.
The ratio of cardiac dihydroxyphenylglycol spillover to cardiac norepinephrine spillover was significantly lower in POTS (5.02±0.98) than in NCS (11.26±2.16, F=5.6, P=0.02) or the overall group of healthy volunteers (8.9±0.89, F=6.4, P=0.015).
Patients with NCS had lower mean arterial levels of plasma epinephrine than did those with POTS (Table 2, t=4.04, P=0.0003) and tended to have lower arterial epinephrine levels than did control patients with chest pain and normal coronary arteries (0.33±0.09 nmol/L, P=0.08). Heart rate did not vary significantly with the arterial plasma epinephrine concentration, even during yohimbine infusion.
Lower-Body Negative Pressure
Low-intensity LBNP did not affect mean arterial pressure or heart rate in the groups with POTS or NCS, nor in a group of 6 healthy volunteers who underwent LBNP during right heart catheterization. Forearm vascular resistance also failed to increase significantly in all 3 groups (Table 3). Forearm norepinephrine spillover, however, increased in all 6 healthy volunteers (P<0.05). The proportionate increase in forearm norepinephrine spillover was smaller in the group of patients with NCS than in the groups of patients with POTS or healthy control subjects.
As expected, standing up for 5 minutes increased pulse rate more in the group with POTS than in that with NCS (Table 3). The groups did not differ in proportionate increments in mean arterial pressure or antecubital venous plasma levels of norepinephrine or epinephrine during orthostasis.
The present results provide evidence that postural tachycardia syndrome and recurrent neurocardiogenic presyncope both involve substantial, different, tonic abnormalities of cardiac sympathetic function, qualifying both conditions as cardiac sympathetic dysautonomias. As discussed below, POTS seems to involve increased and NCS decreased norepinephrine release from intact cardiac sympathetic nerves, without evidence for fixed abnormalities in activity of the cell membrane norepinephrine transporter, norepinephrine synthesis, or sympathetic innervation density in either disorder.
Norepinephrine release from sympathetic nerves and inactivation of released norepinephrine by neuronal reuptake constitute the main determinants of both delivery of norepinephrine to cardiac adrenoceptors and the rate of entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). This explains why, across all subjects and in patients with chronic orthostatic intolerance, supine resting heart rate correlated strongly positively with cardiac norepinephrine spillover and why, in both POTS and NCS, yohimbine-induced increments in heart rate correlated positively with increments in cardiac norepinephrine spillover. The relative tachycardia even during supine rest in POTS therefore seems at least partly to reflect increased norepinephrine delivery to adrenoceptors on myocardial pacemaker cells. In contrast, heart rate during supine rest was unrelated to epinephrine concentrations in arterial plasma, indicating lack of dependence of the resting tachycardia on increased adrenomedullary secretion.
Research about mechanisms of POTS has lent support for a variety of concepts. One is that the excessive postural tachycardia might result from deficient activity of the cell membrane norepinephrine transporter. Findings in a family with postural tachycardia associated with a hypofunctional mutation of the transporter8 and established literature about orthostatic intolerance from treatment with tricyclic antidepressants, which inhibit transporter activity, led to this idea. Acute treatment with the tricyclic antidepressant desipramine has been suggested to provide a neuropharmacologic model of orthostatic intolerance.22 This concept predicts an excessive proportionate increment in plasma norepinephrine levels during exposure to stressors evoking norepinephrine release from sympathetic nerves, such as orthostasis; however, the present findings failed to detect augmented cardiac, forearm, or generalized norepinephrine responses to orthostasis in sporadic POTS. More importantly, as discussed below, we found no evidence for hypofunction of the transporter.
Decreased function of the cell membrane norepinephrine transporter would be expected to diminish cardiac extraction of 3H-norepinephrine, decrease myocardial uptake of 6-[18F]fluorodopamine, and attenuate increments in arterial plasma dihydroxyphenylglycol for given increments in plasma norepinephrine during yohimbine infusion. Values for these well-established indices of uptake-1 activity17,23,24⇓⇓ were normal. Because increased cardiac norepinephrine spillover in POTS seems to occur without decreased cardiac uptake-1 activity, either in the heart or in the body as a whole, the elevated cardiac norepinephrine spillover probably reflected increased release of norepinephrine from sympathetic nerves.
Low ratios of dihydroxyphenylglycol to norepinephrine concentrations in antecubital venous plasma of patients with POTS have been taken to suggest that the syndrome might result from decreased activity of the cell-membrane norepinephrine transporter.25 The finding of a decreased plasma ratio of dihydroxyphenylglycol to norepinephrine does not necessarily indicate inhibition of uptake-1, because under resting conditions most plasma dihydroxyphenylglycol is derived from net leakage of norepinephrine from storage vesicles into the axoplasm in sympathetic nerves, an ongoing process independent of uptake-1.17 Increased exocytotic release of norepinephrine from any cause, therefore, must decrease the concentration ratio of dihydroxyphenylglycol to norepinephrine. Thus, patients with POTS had a low ratio of cardiac dihydroxyphenylglycol spillover to cardiac norepinephrine spillover but normal values for indices of cardiac uptake-1 activity.
According to another concept, POTS results from patchy extracardiac sympathetic denervation, compensatorily activating cardiac sympathetic outflow.26 Because cardiac norepinephrine spillover contributes little to total body norepinephrine spillover, from this notion one would predict decreased total body norepinephrine spillover at baseline or attenuated increments during orthostasis or yohimbine infusion. We found no evidence to support these predictions.
Altered modulation of exocytosis for a given amount of nerve traffic potentially might explain increased norepinephrine release from cardiac sympathetic terminals. For instance, high circulating epinephrine levels might increase occupation of stimulatory presynaptic β2 adrenoceptors,27 or decreased numbers or functions of presynaptic α2 adrenoceptors might attenuate inhibitory modulation of norepinephrine release.17 Because baseline arterial plasma epinephrine levels were approximately normal in patients with POTS and unrelated to heart rate, and yohimbine infusion resulted in augmented rather than attenuated increases in cardiac norepinephrine spillover, neither type of alteration in presynaptic modulation could explain increased cardiac norepinephrine spillover in POTS.
Theoretically, increased innervation density might also augment exocytotic release of norepinephrine for a given amount of nerve traffic. The 6-[18F]fluorodopamine positron emission tomographic scanning results, however, indicated normal cardiac sympathetic innervation density in POTS. The findings of normal cardiac production rates of dihydroxyphenylglycol and dihydroxyphenylalanine would be consistent with normal norepinephrine turnover and synthesis16,17⇓ and therefore also with normal sympathetic innervation density. The preponderance of evidence therefore favors increased cardiac sympathetic nerve traffic, rather than decreased neuronal reuptake, altered modulation of norepinephrine release, adrenomedullary hyperactivity, or increased innervation density, as the basis for increased cardiac norepinephrine spillover and relative tachycardia in POTS.
In marked contrast to patients with POTS, patients with NCS had abnormal, tonically decreased cardiac norepinephrine release. Augmented inhibitory modulation by presynaptic α2 adrenoceptors did not account for the decreased cardiac norepinephrine spillover, because yohimbine infusion did not produce an exaggerated increase in cardiac norepinephrine spillover in NCS. The findings point to decreased cardiac sympathetic nerve traffic as the basis for decreased cardiac norepinephrine spillover in NCS.
The finding that patients with NCS also had attenuated responses of forearm norepinephrine spillover in response to LBNP compared with patients with POTS and healthy control subjects raises the possibility that NCS entails both tonic restraint of cardiac sympathetic outflow and attenuated increments in sympathetic outflow to skeletal muscle during orthostasis. This would fit with findings by Mosqueda-Garcia and colleagues12,13⇓ about inhibition of directly recorded skeletal sympathetic outflow during tilt in patients with neurally mediated syncope.
Both in POTS and NCS, cardiac extraction of 3H-norepinephrine declined when cardiac norepinephrine spillover exceeded more than ≈200 pmol/min. Of several potential causes for this association, which the present findings cannot distinguish, one is that chronic orthostatic intolerance syndromes might feature a form of dynamic attenuation of uptake-1 activity, where neuronal uptake would be normal under resting conditions but decrease during cardiac sympathetic stimulation, such as from saturation of the transporter.
Symptoms in recurrent NCS resembled those in POTS, with high frequencies of orthostatic intolerance, fatigue, disability, chest pain, heat intolerance, and headache. Because we studied only referred patients who agreed to complex and invasive tests, it is possible the group we studied might not have been typical of patients with recurrent presyncope in general.
In both POTS and NCS, during 6-[18F]fluorodopamine infusion, arterial plasma 6-[18F]fluorodopamine levels, normalized for the dose per unit body mass, were higher than in age-matched healthy volunteers. One explanation for this would be low plasma volume. Previous reports have noted hypovolemia in at least a proportion of patients with primary, chronic orthostatic intolerance.28–30⇓⇓
The results lead us to hypothesize that in POTS, cardiac sympathetic stimulation mainly reflects compensatory activation in response to excessively decreased venous return to the heart. There are several possible causes for such decreased venous return, including blood or extracellular fluid volume depletion, venous pooling, extravasation, or local sympathetic denervation. These possibilities are not mutually exclusive, and, as noted above, there is some support in the literature for each. Regardless of the exact cause, the patients’ symptoms would be effects of the volume depletion, with perhaps additional symptoms from cardiac sympathetic activation, such as palpitations or atypical chest pain. In contrast, our hypothesis about NCS is that the patients have tonic restraint of cardiac sympathetic outflow or of norepinephrine release from cardiac sympathetic terminals, producing symptoms such as chronic fatigue and orthostatic or exercise intolerance. Episodically more generalized sympathoinhibition, or failure to increase skeletal sympathetic outflow appropriately, could then evoke hypotension and presyncope.⇓⇓
- ↵Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med. 1998; 105: 15S–21S.
- ↵Iversen LL. The Uptake and Storage of Noradrenaline in Sympathetic Nerves. Cambridge, UK: Cambridge University Press; 1967.
- ↵Furlan R, Jacob G, Snell M, et al. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation. 1998; 98: 2154–2159.
- ↵Mosqueda-Garcia R, Furlan R, Tank J, et al. The elusive pathophysiology of neurally mediated syncope. Circulation. 2000; 102: 2898–2906.
- ↵Jacobsen TN, Morgan BJ, Scherrer U, et al. Relative contributions of cardiopulmonary and sinoaortic baroreflexes in causing sympathetic activation in the human skeletal muscle circulation during orthostatic stress. Circ Res. 1993; 73: 367–378.
- ↵Furlan R, Piazza S, Dell’Orto S, et al. Cardiac autonomic patterns preceding occasional vasovagal reactions in healthy humans. Circulation. 1998; 98: 1756–1761.
- ↵Eisenhofer G, Esler MD, Meredith IT, et al. Sympathetic nervous function in human heart as assessed by cardiac spillovers of dihydroxyphenylglycol and norepinephrine. Circulation. 1992; 85: 1775–1785.
- ↵Goldstein DS, Brush JE Jr, Eisenhofer G, et al. In vivo measurement of neuronal uptake of norepinephrine in the human heart. Circulation. 1988; 78: 41–48.
- ↵Schroeder C, Tank J, Boschmann M, et al. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation. 2002; 105: 347–353.
- ↵Jordan J, Shannon JR, Diedrich A, et al. Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension. 2002; 39: 173–178.
- ↵Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a β2-receptor agonist: a human in vivo study. Circulation. 1999; 99: 2402–2407.