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ORIGINAL ARTICLES |
From the School of Primary Health Care, Monash University, East Bentleigh, Victoria, Australia (J.C.R.); and Baker Heart Research Institute, Prahran, Victoria, Australia (M.E.A., G.L., M.D.E.).
Address correspondence and reprint requests to Marlies Alvarenga, DPsych, MAPS, Faculty of Medicine, Monash University & Cardiovascular Neurosciences Division, Baker Heart Research Institute, 37 Brunswick St, Fitzroy, VIC 3065, Australia. E-mail: Marlies.alvarenga{at}med.monash.edu.au
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ABSTRACT |
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Methods: Thirty-nine people with PD and 39 age- and gender-matched healthy volunteers were studied. In 19 participants with PD, both HRV and plasma noradrenaline kinetics were tested; in 20 with PD and 20 healthy volunteers, HRV measurements only were made, whereas in 19 healthy volunteers, noradrenaline kinetics only was tested. All panic disorder participants completed psychological measures of anxiety sensitivity and state and trait anxiety; healthy volunteers in whom HRV was measured also provided psychological measures.
Results: Sympathetic nervous tone in the heart, based on rates of cardiac noradrenaline spillover, was normal in PD. Noradrenaline and adrenaline plasma clearance and plasma tritiated noradrenaline and adrenaline extraction in transit through the heart, all dependent on the noradrenaline transporter (NET), were reduced in PD. Psychometric testing linked inhibition of anger to this deficit in NET functioning. Anxiety sensitivity was specifically associated with impaired cardiac NET. High- and low-frequency heart rate spectral power was unrelated to all plasma noradrenaline kinetics measurements.
Conclusion: Defective neuronal reuptake of noradrenaline, by augmenting the sympathetic neural signal in the heart, might have a dual effect, sensitizing the heart such as to lead to symptom development (and thus perhaps causing panic disorder) and, second, potentially contributing to adverse cardiac events in established PD.
Key Words: panic disorder • noradrenaline spillover • heart rate variability • neuronal reuptake mechanism • sympathetic nervous system function • heart disease
Abbreviations: PD = panic disorder; CVD = cardiovascular disease; CAD = coronary artery disease; HRV = heart rate variability; LF = low frequency; ADIS-IV = Anxiety Disorders Interview Schedule for DSM-IV; ASP = Anxiety Sensitivity Profile; ASI = Anxiety Sensitivity Index; NET = noradrenaline transporter; SSRI = selective serotonin reuptake inhibiting; HF = high frequency; MAO = monoamine oxidase.
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INTRODUCTION |
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It is perhaps noteworthy that people with PD have consistently shown reduced heart rate variability (HRV; 8–10). Fleet et al. (3) argued that the relationship between PD and reduced HRV constitutes evidence linking PD to a pathophysiological mechanism (reduced cardiac vagus tone), predisposing to heart disease. A decrease in HRV is associated with the development of the clinical endpoints of coronary heart disease (11), suggesting that low HRV might be considered an independent marker of mortality risk (12).
In other clinical contexts, most notably in patients with heart failure, activation of the sympathetic outflow to the heart can lead to the development of ventricular arrhythmias and sudden death (13,14). The risk of fatal CAD events is increased during natural catastrophes such as earthquakes (15), usually attributed to the influence of the preferential activation of the cardiac sympathetic outflow which occurs with acute mental stress (16). Sympathetic nervous activation has been documented during panic attacks in some patients, using direct sympathetic nerve recording (microneurography) and noradrenaline plasma kinetics methodology (17). Attempts have been made to apply circulatory monitoring methods, in particular the measurement of low-frequency (LF) heart rate spectral power, to indirectly measure cardiac sympathetic activity in humans (8,18), but the validity of this technique is in doubt (19,20), and accordingly its value in the investigation of neural mechanisms in PD (21,22) is questioned.
In the present study, we have further tested for what might be the sympathetic nervous mechanisms conferring cardiac risk in PD, applying state-of-the-art radiotracer kinetic methodology. We have evaluated the validity of the less direct neural indices of HRV against these methods. Possible psychological parallels of autonomic nervous system dysfunction in PD were also investigated. The expectancy model of PD (23) posits that sympathetic arousal which is physically or socially harmful underlies the development and maintenance of the frequent panic attacks characterizing this disorder. Anxiety sensitivity is therefore conceptualized as an individual difference variable that amplifies fear and other anxiety reactions in PD (24). We tested for a biological association of sympathoneural indices with this construct.
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METHODS |
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Participants
PD
Participants with PD were recruited via print media. Following an initial telephone screening, suitable candidates underwent a DSM-IV-based structured clinical interview (ADIS-IV; 25) to assess psychopathology. Those who met a primary diagnosis of PD with a minimum severity score of 4 in a 9-point scale ranging from 0 to 8 and who scored at least 2 severity points above other diagnoses were given a general physical examination that focused on the detection of existing cardiac pathology. In the initial screening, patients with evident comorbid depression, common in PD, were explicitly excluded. Of 51 people who met the DSM-IV diagnostic criteria for PD, 39 ultimately participated, the remainder either deciding not to proceed or being excluded from participation because they were unable to discontinue benzodiazepine medication, which was a prerequisite for participation. The mean duration of PD in the participants was 4 years.
Participants were partitioned further, depending on whether they were taking psychotropic medication. Of the 39 participants with PD, 16 were taking selective serotonin reuptake inhibiting (SSRI) medication for their condition, in 9 of whom noradrenaline kinetics measurements were completed. All were compliant with their medication.
Measurement of Noradrenaline Plasma Kinetics
Nine females (mean age = 42.1 years, SD = 11.9) and 9 males (mean age = 49.2 years, SD = 8.4) successfully completed the catheter procedure. Placement of the central venous catheter was not performed successfully in the other PD participant. Ten PD volunteers had a secondary diagnosis of depression, six had a secondary diagnosis of social avoidant disorder, and two had a secondary diagnosis of generalized anxiety disorder. These secondary diagnoses were "mild" as they scored between 0 and 2 points of severity on a 9-point severity scale (ranging from 0 to 8) (25). All participants scoring between 0 and 2 points for depression on the ADIS-IV Likert scale had less than four DSM-IV specified symptoms of depression.
Measurement of HRV
A total of 10 men (mean age = 35.2 years; SD = 7.2) and 10 women (mean age = 38.1 year; SD = 6.4) who did not participate in the catheter-based noradrenaline kinetics study provided HRV and psychosocial data. Seven were taking SSRI medication. Twelve had a secondary diagnosis of depression, five a secondary diagnosis of social avoidant disorder, two a secondary diagnosis of posttraumatic stress disorder, and one, obsessive-compulsive disorder. These diagnoses were mild, scoring between 0 and 2 points on a 9-point severity scale (ranging from 0 to 8).
Healthy Volunteers
Participants with PD were compared with 39 healthy volunteers, aged 20 to 50 years. The healthy volunteers were recruited in parallel with the PD patients. None had an existing medical diagnosis, and all underwent a medical check and a structured clinical interview (ADIS-IV) to confirm their healthy status. Nineteen of these healthy volunteers participated in the catheter-based measurement of noradrenaline kinetics. They did not provide psychological or HRV data. The 20 other healthy volunteers provided psychological and HRV data. In all, the group composition was of 20 females (mean age = 40.5, SD = 14.31) and 19 males (mean age = 34.7, SD = 12.4). To compensate for their time they were paid $75.00.
Research Ethics
Given that this study involved the use of radioisotopes and the placement of a central venous catheter in some participants, in whom testing was not indicated on clinical grounds, comment on research ethics is in order. The central issues in clinical research ethics are the quality (or lack of quality) of the research, the potential for harm to an individual from the experiment, and the degree of safeguarding of the autonomy of the participants.
As to the scientific value of the research and the safety of the procedures, in the present study we investigated aspects of the neural biology of PD which are potentially of considerable clinical significance, using state-of-the-art research methodology for studying the sympathetic nerves of the heart. There is no less invasive method for validly doing this than we applied. In our very extensive research experience with central venous catheters (13,17,26), we have found the procedure to be associated with negligible risk. In the recruitment of the healthy volunteers, the payment offered was modest, not constituting an unethical inducement. The process of written consent, to which an honest, open, and explicit participant information sheet was central, conformed to the standards expected to preserve the autonomy of the participants. In relation to our use of radioisotopes for research purposes, the estimated effective dose from the infused tracer was 1 to 3 mSv, equivalent to less than 12 hours of background radiation, for which the WHO classification is Category 1 (signifying no demonstrable radiation hazard).
Research Procedures
All participants were instructed to avoid nicotine and beverages containing alcohol or caffeine on the day of the biomedical recording and to come to the laboratory after a light breakfast early that morning. Biomedical recording commenced at 1:00 pm.
Psychological Measures
Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV; 25)
This structured clinical interview based on DSM-IV (27) was used to make a clinical diagnosis of PD (25). The ADIS-IV allows for discrimination between anxiety disorders, as well as for the determination of primary and secondary diagnoses based on the participant’s responses and severity scores on measures of symptomatology. Ratings are considered to be clinically significant when they are scored 4 or above on the Likert-type scale.
Anxiety Sensitivity Profile (ASP; 28)
This is a comprehensive measure of the fear of anxiety-related sensations, based on the belief that these sensations can have harmful social or physical consequences. Based on the Anxiety Sensitivity Index (ASI), the ASP consists of 60-items, which comprise four lower-order factors: (i) fear of respiratory symptoms, (ii) fear of cognitive dyscontrol, (iii) fear of gastrointestinal symptoms, and (iv) fear of cardiac symptoms. These lower-order factors load on a single higher-order factor, suggesting that anxiety sensitivity is the product of a general factor with independent contributions from four specific factors (28). The ASP’s lower-order factors have large correlations (r values 
0.50) with the ASI and a modest correlation with the state-trait anxiety inventory, with overlapping variance ranging from 1% to 8%. These correlations indicate the existence of convergent validity between the ASI and ASP, as well as support for the view that anxiety sensitivity and trait anxiety are correlated but distinct constructs (28).
State Trait Anger Expression Inventory (STAXI; 29,30)
This inventory measures the state and trait anger, the latter of which has been demonstrated to consist of angry temperament or the temperamental disposition to experience and express anger without specific provocation, and angry reaction or the propensity to react with anger when treated unfairly, criticized, or frustrated. Three 8-item scales also measure anger-in (the tendency to suppress angry feelings), anger-out (the tendency to express anger outwardly toward other people or objects in the environment), and anger-control (the tendency to control anger by more rational means).
Psychological testing was done in all patients with PD and in healthy subjects, but excluding those participating in the measurements of noradrenaline plasma kinetics.
Spectral Analysis of HRV
The electrocardiogram was recorded continuously for a 10-minute period of supine rest from lead II and digitized on-line at 1000 Hz using an IBM-compatible PC and a data acquisition package, CVMS (McPherson Scientific, Australia) incorporating a 12-bit analogue-to-digital converter (Computer Boards Inc.) (19). Respiratory rate was not measured. The data acquisition system included a variable threshold peak detection technique from which R-R interval was determined. Data segments of 128-second duration were sampled at 2 Hz to create 256-point data sets. For each 10-minute recording, 8 data sets of 256 points overlapping by half were processed. The linear trend was removed from each data set to avoid its contribution to LF power. LF (0.07–0.14 Hz) and high-frequency (0.15–0.50 Hz, HF) spectral bands were scanned. A Hanning window in the time domain was used to attenuate spectral leakage. Spectral analysis was performed using a direct fast Fourier transform. The frequency resolution was 0.0078 Hz and the highest frequency evaluated was 0.5 Hz. The spectra obtained for different data sets was averaged to reduce variance and to sharpen reproducible spectral peaks.
Measurement of Catecholamine Plasma Kinetics
Regional sympathetic nervous system activity can be studied in humans using measurements of noradrenaline release to plasma from individual organs, applying radiotracer isotope dilution methodology (31,32). Direct sympathetic nerve recording techniques (microneurography) can only be applied subcutaneously and do not give access to sympathetic nerves of internal organs such as the heart, a limitation which we have overcome here by using the regional noradrenaline spillover measurement. The relationship which holds in general between the sympathetic nerve firing rate in an organ and the rate of overflow of noradrenaline into its venous effluent provides the experimental justification for using regional noradrenaline spillover as a surrogate for nerve traffic measurements (32). With infusion of tritiated noradrenaline and regional blood sampling from the coronary sinus, neurotransmitter release from the heart can be measured (31,33).
General Procedure
The research procedure was commenced at 1:00 PM, with participants resting in the supine position. They had earlier eaten a standardized light breakfast. Tea, coffee, and alcohol were withheld for a minimum of 12 hours before the study. Total body and cardiac sympathetic function was assessed according to the methods described below. For this purpose, blood samples for plasma catecholamine assay were obtained from a central venous catheter site in the coronary sinus and a brachial arterial cannula. These were percutaneously inserted under local anesthesia. The central venous catheter, a 7F coronary sinus thermodilution catheter (Webster Laboratories, type CCS-7U-90B) introduced via an antecubital venous sheath, was placed with fluoroscopic control in the coronary sinus such as to include the middle cardiac vein drainage (31). Tritiated noradrenaline and adrenaline were infused into a peripheral vein throughout for the determination of plasma catecholamine kinetics (32). Measurements of the spillover of noradrenaline to plasma from the heart and from the body as a whole were used to estimate cardiac and overall sympathetic nerve noradrenaline release rates. Rather than the rate of release of noradrenaline from sympathetic nerve varicosities, the noradrenaline spillover rate gives the rate at which released noradrenaline enters plasma: in humans, in different organs this ranges from approximately 5% to 20% of the noradrenaline release rate (lowest in the heart) (33).
Neurochemical Measures of Sympathetic Nervous Function
The total body noradrenaline spillover rate and adrenaline secretion rate and catecholamine plasma clearances were measured using the radiotracer methods developed in our laboratory (31,32,34). In brief, the method involves the continuous intravenous infusion of a tracer dose of noradrenaline and adrenaline (0.70 mCi/min of 3[H]-noradrenaline and 3[H]-adrenaline, New England Nuclear, Boston) to a steady-state concentration in plasma. The total noradrenaline spillover rate to plasma from sympathetic nerves and the adrenaline secretion rate from the adrenal medulla were derived from isotope dilution and total plasma noradrenaline and adrenaline plasma clearances from the plateau plasma concentration of tracers (32,34).
Whole body rates of noradrenaline plasma spillover and clearance were calculated as follows:
NA plasma clearance = [3H] NA infusion rate (dpm/min)/plasma [3H] NA conc. (dpm/ml).
Plasma NA spillover = [3H] NA infusion rate (dpm/min)/plasma NA specific activity (dpm/pg). The secretion rate and plasma clearance of adrenaline were calculated similarly.
Cardiac noradrenaline spillover was calculated using the following equation:
Cardiac NA spillover = {(NAcs-NAa) + (NAa.NAex)} x CSPF
where NAa and NAcs are the arterial and coronary sinus plasma concentrations of noradrenaline, NAex is the fractional extraction of tracer noradrenaline across the organ, and CSPF is the coronary sinus plasma flow. Coronary sinus plasma flows were derived from thermodilution-determined blood flows and the hematocrit (13).
Catecholamine Assays
Blood samples for the estimation of catecholamines were transferred immediately to ice-chilled tubes containing EGTA and reduced glutathione, centrifuged at 4°C, and the plasma was stored at –70°C before assay. The plasma concentration was determined by high-performance liquid chromatography with electrochemical detection (35). Timed collection of the eluate leaving the detection cell using a fraction collector permitted separation of 3H-labeled noradrenaline and adrenaline for counting by liquid-scintillation spectroscopy. Intra-assay variations were 4.6% for plasma noradrenaline and 6.8% for plasma adrenaline at concentrations of 150 pg/ml and 7.2% and 6.5% for 3H-labeled noradrenaline and adrenaline.
Assessment of Neuronal Noradrenaline Transport
Neuronal noradrenaline uptake in the heart can be assessed by measuring the extraction of plasma tritiated noradrenaline (3H NA) in passage through the heart, and the overflow of tritiated dihydroxphenylglycol (3H DHPG) into the coronary sinus, after reuptake of 3H NA into sympathetic nerves and intraneuronal metabolism by monoamine oxidase (MAO) (Figure 1) Additional information is provided by the extraction of plasma tritiated adrenaline in transcardiac passage (adrenaline is also a substrate for the noradrenaline transporter, NET) and the whole body clearance of adrenaline and noradrenaline from plasma (33,36,37).
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The fractional extraction of tritiated norepinephrine from plasma at steady state during passage through the heart was calculated from the relation:
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where 3H NEA and 3H NECS are the concentrations of tritiated noradrenaline in arterial and coronary sinus plasma. The fractional transcardiac extraction of plasma tritiated adrenaline was calculated similarly.
Statistical Analyses
The assumptions of normality were tested for and met. For analyses examining within and between factors, the assumption of equal variance-covariance matrices was also met. All statistical tests were two-tailed, and statistical significance was generally set at a probability level of .05. However, where multiple comparisons were conducted, 
levels were adjusted to a more conservative 0.01. Despite this, with testing for multiple correlations, the possibility of Type I errors does remain. Post hoc comparisons were carried out using the Scheffé procedure, one of the more conservative post hoc tests (38). Correlational analyses, using Pearson’s product movement correlation coefficient, were conducted in order to ascertain the degree of association between the psychological and biomedical variables. Variables for which there were significant correlations were entered into multiple regression analyses to further test the robustness of the associations. All relevant predictors were entered as a block at the same time.
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RESULTS |
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Neurochemical Measures of Neuronal Noradrenaline Reuptake
The overall clearance of noradrenaline and adrenaline from plasma, the transcardiac extraction of plasma tritiated noradrenaline and adrenaline, and the overflow of tritiated DHPG from the heart to plasma were all lower in PD than in healthy volunteers (Table 2). Using analysis of variance with an value set at 0.01, differences were found in the cardiac extraction rate of tritiated adrenaline (F(2,28) = 8.50, p < .01) and noradrenaline (F(2,28) = 5.84, p < .01). Statistically significant differences were also found for total adrenaline clearance (F(2,28) = 6.81, p < .01) and noradrenaline plasma clearance rates (F(2,28) = 6.96, p < .01). This provides evidence of reduced activity of the neuronal NET) in PD as all, including the adrenaline plasma removal rates, are dependent on NET transport into sympathetic nerves (32). The mean release of tritiated DHPG from the heart in PD was approximately 60% lower than in healthy volunteers (Table 2) (F(2,22) = 3.93, p < .05). Specific intergroup differences were investigated by Scheffé’s procedure. For noradrenaline clearance, the normal control group was significantly different to the unmedicated group (p < .01) but there was no significant difference between the medicated and unmedicated PD groups (p > .05). For all other neurochemical indices, there were no significant differences, as investigated by the Scheffe procedure.
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The SSRI drugs were truly serotonin selective as drug treatment did not reduce catecholamine removal from plasma. To the contrary, noradrenaline and adrenaline total plasma clearance and cardiac radiotracer extractions were marginally, although not significantly, greater in SSRI-treated PD patients (Table 2).
HRV
HF heart rate spectral power was significantly lower in PD patients than in healthy volunteers (Table 3). This was independent of SSRI treatment status. LF spectral values were unremarkable in PD. "Normalized" heart rate spectral power (LF/HF) was significantly elevated in PD, attributable to the smaller denominator.
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Heart rate spectral analysis values were unrelated to all neurochemical measures of sympathetic nervous activity and to the adrenaline secretion rate (Table 4). More specifically, the "gold standard" measure of cardiac sympathetic activity, cardiac noradrenaline spillover, bore no relationship to LF heart rate spectral power (Table 4).
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Psychological Variables
Statistically significant differences were found between the groups for the following psychological variables using ANOVAs with an value set at 0.01. For the anger components, trait anger, a measure of proneness to being easily agitated or upset (F(2,56) = 6.84, p < .01), angry reaction, the likelihood to react with anger when treated unfairly, criticized, or frustrated (F(2,56) = 6.83, p < .01) and anger-in, the tendency to suppress angry feelings (F(2,56) = 6.29, p < .01), significant differences between groups were found. For anxiety sensitivity, the belief that physical sensations could have harmful social or physical consequences (F(2,56) = 24.42, p < .01) significant differences were also found.
To test for the existence of individual intergroup differences, the Scheffé procedure was carried out, which showed that for anxiety sensitivity, the control group differed significantly from the unmedicated panic group (p < .01), with the unmedicated group having the highest anxiety sensitivity levels and the control group having the lowest levels. Anger-in scores were also significantly different between the unmedicated PD group and the healthy control group (p < .01), where the unmedicated sample had the highest anger-in levels and the control group had the lowest levels. However, no significant differences were found between the medicated and unmedicated groups, suggesting that SSRI medication did not have a specific significant effect on these psychological measures.
Correlation of Psychological Variables and Autonomic Nervous System Function
HRV
The relationships between the psychological measures and the spectral components of the HRV signal were explored for the total sample of 39 people with PD and the 20 healthy volunteers in whom HRV measurements were made. The correlation matrix for the two sets of variables showed no statistically significant relationships.
Adrenaline Secretion
Analysis excluded healthy volunteers. Among the 19 PD patients tested, plasma adrenaline concentration was inversely related to anger-out, a measure of the tendency to express anger overtly (r = –0.48, p < .05) and to trait anger, the temperamental disposition to experience and express anger without specific provocation, (r = –0.52, p < .05). A regression analysis with both psychological variables entered as predictors showed that trait anger significantly inversely predicted levels of plasma adrenaline concentration for people with PD (ß = –0.43, t = –2.21, p = .04). There were nonsignificant trends for anger-out to also do so (ß = –0.39, t = –1.99, p = .06). Total adrenaline secretion rate was inversely correlated with angry reaction, the propensity to react with anger on the perception of being treated unfairly, criticized, or frustrated (r = –0.49, p < .05), and with trait anger (r = –0.52, p < .05). In multiple regression analyses, they did not, however, either together or individually significantly predict total adrenaline secretion rate.
Neuronal Noradrenaline Uptake
Among the 19 PD subjects in whom data were available, significant inverse correlations were found between anger control (the tendency to control anger by rational means) and adrenaline (r = –0.52), and noradrenaline (r = –0.54) plasma clearance rates (greater control of anger was related to lower plasma catecholamine clearances). An analogous finding, also linking reduced NET activity to anger suppression, was the significant inverse correlation existing between anger-in levels and tritiated DHPG spillover rates from the heart (r = –0.57, p < .05). Greater suppression of anger was related to lower spillover rates of tritiated DHPG in people with PD. Consequently, a regression analysis was carried out to explore the linear model fit for the significant associations. The relationships between anger control and adrenaline clearance (F(1,16) = 3.48, p> .05), and between anger control and noradrenaline clearance rates (F(1,16) = 2.54, p > .05) were nonsignificant trends only. The regression analyses, however, showed that the relationship between anger-in and tritiated DHPG spillover was statistically significant (ß = –0.57, t = 2.71, p < .05).
Correlation analysis also showed an inverse relationship between anxiety sensitivity and cardiac plasma tritiated noradrenaline extraction (r = –0.49, p < .05), indicating that lower rates of cardiac noradrenaline reuptake, which tend to promote greater persistence of noradrenaline in the synaptic space after its release from the sympathetic nerves of the heart (32), are related to greater fear of anxiety-related sensations.
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DISCUSSION |
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Autonomic nervous system abnormalities were also studied using HRV methodology. Our measures of heart rate spectral power documenting reduced HF spectral power and an increased LF/HF normalized spectral power ratio (driven by the lower denominator) suggested the existence of reduced influence of the cardiac vagal nerve in PD. This has also been documented in prior reports (9,41). We found LF heart rate spectral power to be unremarkable in PD. LF heart rate spectral power seems to be driven by the arterial baroreflex, being closely linked to systolic blood pressure changes and to the rhythmic variability of Mayer pressure waves (42). In contrast with an earlier report (43), we find the sensitivity of the sympathetic arterial baroreflex (derived from microneurography recordings) to be actually increased in PD (44,45), which might have been expected to increase LF heart rate spectral power.
LF variability in heart rate does not, of course, strictly provide a measure of the rate of firing of the cardiac sympathetic nerves, despite widespread and often uncritical interpretation of the variability measurement in this way (19,42). This has been previously established in a wide range of clinical contexts (19). This study is also the first to simultaneously perform measurements of HRV and spectral analysis with the neurochemical determination of cardiac sympathetic activity in PD. Again, as in these other contexts, the variability measures were unrelated to those of cardiac noradrenaline spillover. HRV measures have validity for assessing cardiac vagal but not cardiac sympathetic neural outflows (19,20,42).
In untreated patients with PD, we found unequivocal evidence that the neuronal reuptake of noradrenaline is impaired. This is unlikely to represent an adaptive down-regulation of the NET gene occurring in response to surges of sympathetic activity during panic attacks. Such an abnormality would be expected to magnify sympathetically mediated responses, particularly emotionally driven responses in the heart where noradrenaline inactivation is so dependent on neuronal reuptake (33), perhaps causing sensitization to cardiac symptom development and predisposing to the development of PD. Cardiac patients with palpitations from recurrent supraventricular tachycardias (46) and those with implantable cardiac defibrillators (47), which are prone to discharge in error, certainly are prone to develop PD. Augmentation of the sympathetic neural signal in the heart, by impairment of neuronal noradrenaline reuptake, additionally could increase cardiac risk, predisposing to the development of cardiac tachyarrhythmia (13).
The measures of sympathetic activity (plasma noradrenaline concentration and total and cardiac noradrenaline spillover) were all marginally but not statistically significantly lower in the SSRI-treated than untreated PD patients. Although the difference was less for the more specific spillover values (approximately 22%) than for the plasma concentration of noradrenaline, some degree of lowering of sympathetic nervous activity, either by a specific SSRI drug effect or consequent on clinical improvement, is possible. It was of interest that no material differences were found between medicated and unmedicated PD patients in the measures of neuronal noradrenaline uptake indices, suggesting that the selective serotonin reuptake blockers administered were truly selective, without effect on the noradrenaline uptake mechanisms in the doses used in people with PD.
DNA sequencing studies of the norepinephrine transporter gene in PD are in progress to search for a genetic explanation of this phenotype of impairment of neuronal noradrenaline reuptake. To date, no NET gene loss of function coding region mutations have been detected, so the basis of the NET impairment remains unknown. It is perhaps noteworthy that this phenotype of impaired neuronal noradrenaline reuptake is also well documented in essential hypertension (48) and the postural tachycardia syndrome (49), both being conditions which commonly coexist with PD (41,49,50). In preliminary unpublished observations, we detect epigenetic silencing of the NET gene in the postural tachycardia syndrome due to promoter region DNA methylation. We now plan to extend our search for causes of reduced NET function in PD to testing for similar epigenetic silencing of the NET gene.
This study is among the first to test for a relation of psychological variables to measures of autonomic nervous system functioning in PD. In retrospect, it was regrettable that we failed to perform systematic psychological testing also in the healthy volunteers in whom catecholamine kinetics was measured. Our results in PD document a relationship between NET activity in the heart and anxiety sensitivity, suggesting that augmentation sympathetic nerve firing in the heart by an impairment of neuronal noradrenaline reuptake may lead to perceptions which are potentially threatening in people with PD, leading to fear of autonomic arousal (i.e., anxiety sensitivity). This raises the suggestion that there may be a biological basis for high anxiety sensitivity, which predisposes to the development of PD (28). We also found that higher levels of trait anger were linked with low plasma concentrations of adrenaline. It may be pertinent that acutely provoked anger tends to cause sympathetic nervous activation without secretion of adrenaline (51), but the physiological mechanism behind the inverse relationship we found remains unclear.
Of note also was the finding that the clearance of both catecholamines from plasma was inversely related to anger control (the tendency to control anger by rational means). This suggests a presently inexplicable relationship of anger control to reduced capacity for the NET to remove adrenaline and noradrenaline from plasma because the transporter provides a major mechanism for the plasma clearance of both catecholamines (32). Suppression of anger (anger-in) was also linked to another index of NET function, evident in an inverse relation of this psychological dimension to spillover of tritiated DHPG from the heart. DHPG is the intraneuronally produced metabolite of infused tritiated noradrenaline, produced in sympathetic nerves after neuronal uptake and subsequent conversion by MAO. Given the previous published evidence linking genetic abnormality in MAO to behavior (52,53), however, the observation concerning DHPG could possibly be via reduced enzymatic conversion of noradrenaline rather than impaired neuronal noradrenaline uptake. The relationship of suppressed anger to this biochemical deficit needs further investigation.
In summary, we found a deficit in the neuronal reuptake mechanism of noradrenaline in people with PD. By augmenting cardiac sympathetic neural signals this might, perhaps, provide a biochemical basis for several phenomena:
We gratefully acknowledge the participants who volunteered to be part of this study; the lead cardiologist, Professor David Kaye; technical support, Dr. Bronwyn Kingwell, Dr. Jacqueline Hastings, Ms Flora Socratous, and Ms Melissa Formosa.
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Received for publication January 12, 2005; revision received September 26, 2005.
DOI:10.1097/01.psy.0000195872.00987.db
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