Clin Auton Res DOI 10.1007/s10286-014-0227-0
RESEARCH ARTICLE
Visceral sensitization in postural tachycardia syndrome Ramesh K. Khurana
Received: 6 September 2013 / Accepted: 24 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Objective Both psychogenicity and organicity have been asserted in postural tachycardia syndrome (PoTS). We studied the genesis of palpitations to dissect the biologic nature of PoTS. Methods Eleven PoTS patients and 10 control subjects were asked to discriminate types of palpitations when supine and in response to two sympathetic stimuli [Valsalva maneuver (VM) and 10-min head-up tilt (HUT)] and one vagolytic stimulus (atropine administration). Participants rated the 10 items of the somatosensory amplification scale to assess symptom exaggeration. Their time-dependent heartbeat counts were compared against EKG data to study ability to perceive heartbeat. Results Maximal heart rate increase (mean ± SE) over baseline (bpm) did not differ statistically between patients and controls (VM, 39.3 ± 4.7 versus 28.9 ± 3.9, respectively; p = 0.11; HUT, 42.4 ± 4.2 versus 34.7 ± 2.6, respectively; p = 0.14; and atropine, 47.8 ± 2.5 versus 52.0 ± 2.1, respectively; p = 0.22). Palpitations were more frequent in patients at baseline (55 versus 0 %, p = 0.006) and with VM (82 versus 10 %, p = 0.001) and HUT (64 versus 0 %, p = 0.002), but not with atropine (64 versus 60 %, respectively; p = 0.86). Patients discriminated more types of palpitations than did controls (seven versus three types). No difference was observed in somatosensory amplification or heartbeat perception. Interpretation Palpitations were independent of tachycardia and were predominantly sympathetically mediated. The lack of somatosensory amplification militated against R. K. Khurana (&) Department of Medicine, MedStar Union Memorial Hospital, 201 East University Parkway, Baltimore, MD 21218, USA e-mail: [email protected]
psychogenicity. PoTS patients were not superior in detecting peripheral cardiac sensation. However, patients were superior in discriminating palpitations qualitatively in response to individual stimuli, suggesting central visceral sensitization. Explanation of the nature of symptoms and pharmacologic management may be of therapeutic benefit. Keywords Postural tachycardia syndrome Tilt-table test Valsalva maneuver
Introduction Postural tachycardia syndrome (PoTS) is recognized as a constellation of predominantly orthostatic symptoms including dizziness, palpitations, shortness of breath, chest pain, anxiety, and fatigue [2, 17]. Multiplicity and severity of symptoms and significant disability in PoTS exceed demonstrable medical disease, suggesting psychogenicity. This assumption has led to long-standing scientific debate about the biologic nature of PoTS. In 1918, Fraser and Wilson [6] administered intravenous adrenaline in 10 patients with DaCosta’s syndrome (an alternative name for PoTS) and four control subjects. Control subjects developed only transient pallor of the face. Four of ten patients manifested no symptom after receiving normal saline. With administration of adrenaline, all 10 patients developed pallor of face followed by flushing, feeling of generalized warmth, throbbing in the chest and head, and constrictive feeling in the chest, suggesting organicity of PoTS. In a study of a larger cohort of 300 patients in 1941, Wood [25] concluded that DaCosta’s syndrome should be regarded as an emotional reaction of psychoneurotic subjects. BenrudLarson and colleagues [3] attributed significant disability in PoTS to catastrophic cognitions, somatic vigilance, and
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anxiety sensitivity. This diagnostic dilemma can lead to inappropriate diagnosis and treatment of this debilitating condition. PoTS is a syndrome with inherent heterogeneity, disabling symptoms, and no single confirmed etiology [9]. Therefore, we studied palpitations, a common symptom of PoTS. Palpitations are experienced by up to 89 % of patients with PoTS [22, 25]. Palpitation, a sensory symptom, is broadly defined as an unpleasant awareness of the heartbeat. Palpitations are experienced in a variety of ways, from fluttering to pounding, under physiologic or pathologic conditions. Physiologic conditions include exercise, emotional reaction, stress, and consumption of nicotine or caffeine. Pathologic disorders associated with palpitations are cocaine and ephedrine use, anemia, hyperthyroidism, hypoglycemia, pheochromocytoma, and cardiac disorders of rhythm, rate, and contractility [4]. Palpitation is a complex bodily sensation involving visceral, somatic, cognitive, and affective components. Heartbeat, a marker for palpitations, although not as complex, can be measured precisely and easily. We used heartbeat as a measure of visceral perception to dissect the psychologic versus organic nature of symptoms in PoTS. We hypothesized that palpitations in PoTS are heart rate dependent and that patients amplify their visceral sensations. We also hypothesized that patients have superior heartbeat perception ability. Heart rate was altered quantitatively and qualitatively with two physiological stimuli [Valsalva maneuver (VM) and head-up tilt] and one pharmacological stimulus with atropinization to compare effect on palpitations in patients and healthy controls. With simple validated measures, we compared somatovisceral amplification using a scale of somatosensory amplification and cardiac perception accuracy using a heartbeat perception test.
system such as diabetes mellitus, cardiovascular disease, or cardiac arrhythmias. Hematologic screening; renal, liver, thyroid, and adrenal tests; sedimentation rate; serum protein electrophoresis; vitamin B12 levels; hemoglobin A1c; and urinary porphyrin determination were normal. Electrocardiography, echocardiography and 24-h Holter monitoring were normal in all patients. All patients had undergone cardiovagal, adrenergic, and sudomotor tests to document the diagnosis of PoTS. Control subjects were not taking any medication. PoTS patients were off all medications for 7 days. All participants were instructed to fast overnight and to avoid analgesics, caffeine, nicotine, and exercise on the day of testing. The participants were studied in the morning after a light breakfast. They lay supine in a room at 22 °C with head elevated comfortably at a 15° angle. They were familiarized with the equipment and the nature of the procedures. Blood pressure and heart rate were monitored noninvasively with a beat-to-beat blood pressure plethysmograph (Finapres, Ohmeda 2300) and heart rate monitor, respectively. An intravenous line was started in the antecubital vein with the use of a 19-gauge needle and heparin lock solution. The testing was completed in a 2-h session. Somatosensory amplification scale The somatosensory amplification scale (SSAS) was used to study self-reported sensitivity to normal somatic and visceral sensation. The participants used a five-point scale to rate the degree of discomfort associated with 10 ‘‘benign’’ sensations. This test quantifies the intensity of various symptoms and does not involve the subjective judgment of a physician. The test–retest reliability and internal consistency of SSAS have been demonstrated [1]. Each participant’s rating of each of the 10 items were added to obtain a somatosensory amplification score. A higher score indicated greater symptom amplification.
Methods Heartbeat perception test Participants The Institutional Review Board approved the study and all participants gave informed consent. Ten control subjects and 11 PoTS patients participated in the study. No controls had history of systemic disease, mitral valve prolapse, cardiac arrhythmia, vasovagal syncope, psychiatric disease, or pregnancy. All PoTS patients fulfilled the diagnostic criteria including symptoms of orthostatic intolerance, [6 months history, orthostatic tachycardia C30 bpm in response to 10 min of head-up tilt (HUT) or an absolute heart rate [120 bpm without orthostatic hypotension. Patients had no past history of panic disorder or of any systemic illness likely to affect the autonomic nervous
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The heartbeat perception test (HBPT) is a standard noninvasive measure of interoceptive awareness. It is a mental tracking paradigm developed by Schandry [23] to assess an individual’s objective ability to detect the heartbeat. Subjects, in supine position, were asked to take off their watch, to not count their pulse or hold their breath, and to look at the blank wall to the left. The finger cuff of the Finapres blood pressure instrument was removed. A start and stop signal between the investigator and the participant was established before starting timed trials. Before the test, a familiarization task was administered for 12 s. Participants were unaware of the length of the counting phases. The participants silently counted the heartbeats they felt in their
Clin Auton Res
body during signaled intervals of 35, 25, and 45 s with 30-s intervals between each phase. After each trial, the subjects reported the number of counted heartbeats. No performance feedback regarding degree of accuracy was provided. Actual heart rate data were derived from counts of the number of R waves in each segment of the electrocardiogram. Both counted and actual heartbeat responses were recorded. HBPT was quantified as an error score (inaccuracy). Degree of inaccuracy was calculated as the difference between reported and actual number of heartbeats divided by the actual number of heartbeats and multiplied by 100. The result was expressed as a percentage error score. Mean error score was derived by averaging the results of three trials. Symptom stimulation The symptom of palpitations was recorded at rest and in response to physiologic and pharmacologic stimuli. Participants were asked to select the type of palpitation from one of eight previously identified varieties: pounding, thumping, heart beating in the neck, racing, skipping, stopping, fluttering, and heart beating irregularly [24]. Participants rated palpitation severity on a visual analog scale of 1–10. Palpitation severity was classified arbitrarily based on the severity scale as mild, 1–3; moderate, 4–7; and severe, 8–10. Two sympathoexcitatory physiologic stimuli were used: the VM and the HUT. The VM was performed with the subject in supine position. The participant initiated the maneuver at the end of normal inspiration, raised expiratory pressure quickly to 40 mmHg, and maintained it for 15 s [13]. In the HUT, the participant was loosely strapped across chest and thighs to an electrically operated table with foot support. Baseline measurements of blood pressure and heart rate were obtained for 5 min before the table was tilted upright to 90° and maintained for 10 min [14]. Atropine was used for pharmacologic vagolysis to increase the heart rate. An intravenous bolus of atropine, 0.03 mg/kg body weight, was administered and heart rate was continuously monitored [12]. The peak (not steady state) heart rate rise, over the 30-s average baseline, in response to various stimuli was compared between control subjects and patients.
and HBPT for 45 s then rest for 3 min. VM was administered, and the investigator asked about palpitations immediately after cessation of expiratory strain. The individual rested for 3 min. HUT was administered for 10 min, during which the individual enumerated all symptoms as they occurred, including palpitations, followed by rest for 10 min. Atropine was then administered, and the investigator asked about palpitations during this test and observed until heart rate began to decline. Statistical analysis The number of study subjects was ascertained by power analysis, which found that 10 subjects in each group would be adequate to detect an increase in heart rate of at least 20 beats per minute with a power of 80 % at the 0.05 probability level assuming a standard deviation of 20 beats per minute. Data were compared using an unpaired two-sided t test and one-way ANOVA. Statistical analysis was done using Statgraphics.
Results The mean age of control subjects was 27.6 ± 4.4 (mean ± SD) years and 8 of 10 (80 %) were female. The mean age of PoTS patients was 31.9 ± 9.4 (mean ± SD) years and 8 of 11 (73 %) were female. Baseline HR was significantly higher in PoTS patients than in healthy control subjects (79 ± 2 versus 70 ± 2 bpm, p \ 0.01). Differences in heart rate increase in response to three stimuli were not statistically significant (Table 1). PoTS patients had significantly greater occurrence of palpitations compared with control subjects at baseline (55 versus 0 %, p = 0.006), after VM (82 versus 10 %, p = 0.001), and after HUT (64 versus 0 %, p = 0.002). No difference in occurrence of palpitations was observed after atropine administration (patients, 64 %; control subjects, 60 %; p = 0.86) (Tables 2 and 3). Symptom severity was higher in patients than in control subjects. At baseline, control subjects had no palpitations, whereas palpitations of PoTS patients were moderate to severe (severity, 4–8). In Table 1 Peak heart rate increase in response to stimuli
Experimental design
Test
Heart rate increase (bpm) (mean ± SE) Control subjects
Instrumentation was done, followed by instruction and trials of 12-s HBPT and 15-s VM. The individual rested for 15 min. The investigator asked about palpitations at rest and then administered the somatosensory amplification scale, followed by rest for 5 min. HBPT was administered for 25 s then rest for 30 s, HBPT for 35 s then rest 30 s,
p value
Patients
VM
28.9 ± 3.9
39.3 ± 4.7
0.11
HUT Atropine
34.7 ± 2.6 52.0 ± 2.1
42.4 ± 4.2 47.8 ± 2.5
0.14 0.22
Bpm Beats per minute, SE standard error, VM Valsalva maneuver, HUT head-up tilt
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Clin Auton Res Table 2 Palpitations: control subjects No.
Baseline
VM
Grade
HUT
Atropine
Grade
1
No
No
–
No
Racing
3
2
No
No
–
No
No
–
3
No
No
–
No
Racing
8
4
No
No
–
No
Racing
4
5
No
No
–
No
No
–
6
No
No
–
No
No
–
7
No
No
–
No
2
8
No
No
–
No
Heart beating in neck No
9
No
Thumping
2
No
Racing
4
10
No
No
–
No
Racing
4
–
that questions pertaining to pollutants and prolonged bruising elicited significantly elevated responses in PoTS patients. No difference between groups was observed in response to questions pertaining to autonomic dysfunction such as ambient temperature tolerance and hunger contractions. The ability of control subjects to detect their heartbeat was variable with error scores ranging from 1.4 to 40.4 %. Error scores in PoTS patients were distributed over an extremely wide range, from 3 to 104 %. No statistically significant difference in percentage error scores between groups was found [control subjects, 14.4 ± 3.5 (mean ± SE); patients, 25.2 ± 9.8; p = 0.31].
VM Valsalva maneuver, HUT head-up tilt, – not applicable
Discussion response to VM and HUT, control subjects had no or mild palpitations whereas most PoTS patients had mild to severe palpitations. Atropine produced mild to severe (severity, 2–8) palpitations in both control subjects and PoTS patients. Control subjects discriminated three different types of palpitations (5 racing, 1 heart beating in neck, and 1 thumping) (Table 2). Patients discriminated seven different types of palpitations (12 racing, 8 pounding, 3 heart beating in neck, 3 fluttering, 2 thumping, 1 skipping, and 1 irregular heartbeat) (Table 3). PoTS patients also appeared to discriminate different types of palpitations with different stimuli (Table 3). Cardiac rhythm was normal during the study. There was no difference in overall somatosensory amplification between normal subjects and controls [14.4 ± 2.3 (mean ± SE) versus 17.5 ± 1.5, respectively; p = 0.27]. Analysis of individual items (Table 4) showed Table 3 Palpitations: PoTS patients
VM Valsalva maneuver, HUT head-up tilt, – not applicable
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No.
Baseline
1
Skipping
2
Racing
3 4
No Racing
5 6
Grade
The current data show that palpitations in PoTS are of organic origin. PoTS patients and control subjects did not differ in palpitation response to atropine-induced tachycardia, but PoTS patients had significantly more palpitations compared with healthy controls in response to the Valsalva maneuver and head-up tilt, two stimuli that cause sympathetic excitation. These findings, along with the lack of statistically significant difference in peak heart rate response between the groups, suggest that palpitations in PoTS are mediated predominantly by sympathoexcitatory stimuli and are independent of tachycardia. PoTS patients did not amplify their somatic and visceral sensations compared with control subjects, indicating that they are not predisposed to exaggerating every symptom and militating against psychologic origin. PoTS patients also did not display superior ability to perceive heartbeat, suggesting normal peripheral visceral input. However, patients had greater ability to discriminate the type of palpitation
VM
Grade
HUT
Grade
Atropine
Grade
4
Thumping
10
No
–
Racing
7
6
Fluttering
2
Irregular heartbeat
5
No
–
– 6
Pounding Pounding
6 9
Racing No
6 –
No No
– –
Racing
4
No
–
No
–
Racing
2
Racing
8
Pounding
6
Pounding
3
Heart beating in neck
6
7
No
–
Pounding
6
Racing
8
Racing
5
8
Fluttering
8
Pounding
7
Racing
8
Heart beating in neck
8
9
No
–
No
–
No
–
Fluttering
4
10
No
–
Racing
3
Racing
5
Pounding
5
11
No
–
Thumping
6
Pounding
4
Heart beating in neck
7
Clin Auton Res Table 4 Response (mean ± SE)
to
Question
somatosensory Control subjects (n = 10)
amplification Patients (n = 11)
scale p value
When someone coughs, it makes me cough too
0.20 ± 0.13
0.27 ± 0.14
0.71
I cannot stand smoke, smog, or pollutants in the air I am often aware of various things happening within my body
1.40 ± 0.31
2.70 ± 0.47
0.03
2.20 ± 0.44
2.36 ± 0.24
0.74
When I bruise myself, it stays noticeable for a long time
1.40 ± 0.34
2.64 ± 0.34
0.02
Sudden loud noises really bother me
1.50 ± 0.40
1.91 ± 0.34
0.45
I can sometimes hear my pulse or my heartbeat throbbing in my ear
1.10 ± 0.28
2.00 ± 0.38
0.08
I hate to be too hot or too cold
2.40 ± 0.43
1.54 ± 0.25
0.33
I am quick to sense the hunger contractions in my stomach
2.40 ± 0.43
1.54 ± 0.25
0.09
Even something minor like an insect bite or a splinter really bothers me
0.90 ± 0.34
0.36 ± 0.20
0.19
I have a low tolerance for pain
0.90 ± 0.43
0.72 ± 0.27
0.73
14.40 ± 2.33
17.45 ± 1.49
0.27
Total
compared with control subjects, favoring visceral hypersensitivity and a central origin of PoTS symptoms. PoTS patients share several symptoms with panic disorder and anxiety including palpitations, dizziness, chest pain, shortness of breath, and tremulousness. Benrud-Larson and colleagues assigned a significant role to catastrophic cognitions, somatic vigilance, and anxiety sensitivity in causing disability in PoTS [3]. Another study using the Acute Panic Inventory (API), a validated 17-item scale to assess severity of panic symptoms, demonstrated significantly elevated scores in PoTS patients (26.32 ± 2.34 SE) compared with normal subjects (0.8 ± 0.28.SE) [11]. However, attempts to provide further scientific confirmation of a ‘‘psychological’’ disorder beyond validated questionnaires have yielded negative results. For example, in one study [10], 11 patients and 11 control subjects were subjected to three panic provoking stimuli: 10-min head-up tilt, isoproterenol infusion, and 0.5 M racemic sodium lactate infusion. Sodium lactate, an established experimental precipitant of panic in patients with panic disorder, failed to produce panic symptoms in
PoTS. None of the stimuli produced increased API scores in the cognitive psychological domain essential to the diagnosis of panic disorder, such as fear of dying, fear in general, sense of unreality, and feeling detached. Masuki et al. [16]. found no correlation between lower body negative pressure-induced tachycardia and the psychological variables of anxiety sensitivity, somatic vigilance, and catastrophic cognitions, indicating that anxiety is not the primary cause for the excessive orthostatic tachycardia. Using the Beck Anxiety Inventory and the Anxiety Sensitivity Index, Raj and colleagues [21] showed that patients were moderately anxious but did not exhibit a high level of anxiety sensitivity. The authors found no significant correlation of supine, upright, or change in norepinephrine with the Beck Anxiety Inventory. The cited data, the lack of somatosensory amplification demonstrated in the current study, and the absence of reported improvement or amelioration of the syndrome with isolated psychological management fail to support the psychologic origin of palpitations. Palpitations in PoTS are mediated predominantly by sympathetic excitation independently of tachycardia. This interpretation is supported by the lack of difference between the groups in palpitation frequency and severity after chemical vagolysis, the observation that only one control subject felt palpitations in response to VM or HUT, and the significantly higher incidence of palpitations in patients with VM and with HUT despite the lack of statistical difference in peak heart rate increase between the groups. A study by Raj and colleagues showing a significant decrease in palpitations with beta adrenoreceptor blockade also supports this contention [20]. Sympathetic excitation is likely to be of cerebral origin. Functional magnetic resonance imaging during VM recruits central autonomic pathways, which are critical for interoceptive awareness, including the hippocampus, amygdala, brainstem, and insular and lateral frontal cortices [8]. Moreover, peripherally released catecholamines are generally unable to penetrate the developed blood–brain barrier [15]. The lack of difference between groups in degree of inaccuracy at heartbeat perception in the current study suggests a similar peripheral input. Almost all patients discriminated palpitations by type compared with one control subject despite identical stimuli. This ability to discriminate the quality of palpitations in response to individual stimuli favors altered central processing and visceral hypersensitivity. Potential locations for visceral hypersensitivity include sensory receptors in the cardiovascular system, extrinsic sensory afferent neurons, spinal nociceptive neurons, medulla, midbrain raphe, hypothalamus, and cortex [2, 5, 19]. In the current study, palpitations were differentially observed in PoTS patients during sympathetic stimulation, whereas the effects of vagolytic
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stimulus were similar to those observed in control subjects. Such differential effects depending on the mode of induction of tachycardia argue against sensitization of spinal neurons, which should have responded identically to both types of tachycardia. Therefore, higher levels of the neuraxis (e.g., insular cortex [2, 18]) or multilevel involvement is the most likely explanation. Although visceral sensitization can be maintained by tonic impulse input from the heart and by facilitation from the brain to spinal cord (enhanced afferent processing [19]), the visceral responses cannot be elaborated into a discriminatory component solely through peripheral action. For discrimination of visceral response, the neocortex must work conjointly with the insular cortex and the hippocampus [7]. PoTS is a heterogeneous disorder [9], and the concept of visceral sensitization may not apply to every subset of PoTS. Palpitations did not occur in all patients in this study. The data were partly dependent on answers to indirect measures. One cannot be sure that during HBPT, the subjects were not guessing their average heart rate without actually attending to the heartbeats. Because of the limited number of PoTS patients available for study, the study had power to detect only relatively large differences. A study with objective correlates such as fMRI in a larger number of patients would provide more information. Visceral sensitization helps to explain (1) the phenotype of PoTS despite the underlying heterogeneity of multiple etiologies, (2) a poor correlation between the severity of symptoms and the extent of hemodynamic parameters, (3) multiple and severe symptoms lacking objective correlation, and (4) persistence of orthostatic symptoms despite adequate control of heart rate. PoTS patients should be reassured that unusual visceral sensations (such as feeling pulsations in fingertips or eyeballs) are caused by visceral hypersensitivity and that sympathetic stimuli may precipitate or aggravate palpitations. The current study suggests that drugs that enhance central inhibition or reduce excitation may be useful in ameliorating PoTS symptoms. Acknowledgments I thank Norman Dubin, PhD., for statistical analysis and Lyn Camire, MA, ELS, for editorial assistance. Conflict of interest
The author reports no conflict of interest.
References 1. Barsky AJ, Wyshak G, Klerman GL (1990) The somatosensory amplification scale and its relationship to hypochondriasis. J Psychiatr Res 24:323–334 2. Benarroch EE (2012) Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 87:1214–1225 3. Benrud-Larson LM, Sandroni P, Haythornthwaite JA et al (2003) Correlates of functional disability in patients with postural
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tachycardia syndrome: preliminary cross-sectional findings. Health Psychol 22:643–648 Brugada P, Gursoy S, Brugada J et al (1993) Investigation of palpitations. Lancet 341:1254–1258 Cervero F (1995) Visceral pain: mechanisms of peripheral and central sensitization. Ann Med 27:235–239 Fraser F, Wilson RM (1918) The sympathetic nervous system and the irritable heart of soldiers. Br Med J 2:27–29 Gantt WH (1960) Cardiovascular component of the conditional reflex to pain, food and other stimuli. Physiol Rev Suppl 4:266–291 Henderson LA, Macey PM, Macey KE et al (2002) Brain responses associated with the Valsalva maneuver revealed by functional magnetic resonance imaging. J Neurophysiol 88:3477–3486 Khurana RK (1995) Orthostatic intolerance and orthostatic tachycardia: a heterogeneous disorder. Clin Auton Res 5:12–18 Khurana RK (2006) Experimental induction of panic-like symptoms in patients with postural tachycardia syndrome. Clin Auton Res 16:371–377 Khurana RK, Craig FW, Lynch JJ (2002) Panic symptoms in patients with orthostatic intolerance and orthostatic tachycardia. Neurology 58:A346 Khurana RK, Jones AD (1999) Assessment of minimum vagolytic dose of atropine. Neurology 52:A343 Khurana RK, Mittal D, Dubin NH (2011) Valsalva maneuver: shortest optimal expiratory strain duration. J Commun Hosp Int Med Perspect 1:7015. doi:10.3402/jchimp.v1i2.7015 Khurana RK, Nicholas EM (1996) Head-up tilt table test: how far and how long? Clin Auton Res 6:335–341 Kostrzewa RM (2007) The blood-brain barrier for catecholamines: revisited. Neurotox Res 11:261–271 Masuki S, Eisenach JH, Johnson CP et al (2007) Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety. J Appl Physiol 102:896–903 Mathias CJ, Low DA, Iodice V et al (2012) Postural tachycardia syndrome: current experience and concepts. Nat Rev Neurol 8:22–34 Oppenheimer SM, Gelb A, Girvin JP et al (1992) Cardiovascular effects of human insular cortex stimulation. Neurology 42:1727–1732 Price DD, Craggs JG, Zhou Q et al (2009) Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: evidence from human psychophysics, animal models, and neuroimaging. Neuroimage 47:995–1001 Raj SR, Black BK, Biaggioni I et al (2009) Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more. Circulation 120:725–734 Raj V, Haman KL, Raj SR et al (2009) Psychiatric profile and attention deficits in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry 80:339–344 Sandroni P, Opfer-Gehrking TL, McPhee BR et al (1999) Postural tachycardia syndrome: clinical features and follow-up study. Mayo Clin Proc 74:1106–1110 Schandry R (1981) Heart beat perception and emotional experience. Psychophysiology 18:483–488 Spratt KA, Michelson EL (2005) Evaluation of the patient with palpitations and non-life-threatening cardiac arrhythmias. In: Cardiology for the primary care physican, 4th edn. Current Medicine LLC, Philadelphia, pp 77–84 Wood P (1941) Da Costa’s syndrome: aetiology lecture III. Br Med J 1:845–851
RESEARCH ARTICLE
Visceral sensitization in postural tachycardia syndrome Ramesh K. Khurana
Received: 6 September 2013 / Accepted: 24 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Objective Both psychogenicity and organicity have been asserted in postural tachycardia syndrome (PoTS). We studied the genesis of palpitations to dissect the biologic nature of PoTS. Methods Eleven PoTS patients and 10 control subjects were asked to discriminate types of palpitations when supine and in response to two sympathetic stimuli [Valsalva maneuver (VM) and 10-min head-up tilt (HUT)] and one vagolytic stimulus (atropine administration). Participants rated the 10 items of the somatosensory amplification scale to assess symptom exaggeration. Their time-dependent heartbeat counts were compared against EKG data to study ability to perceive heartbeat. Results Maximal heart rate increase (mean ± SE) over baseline (bpm) did not differ statistically between patients and controls (VM, 39.3 ± 4.7 versus 28.9 ± 3.9, respectively; p = 0.11; HUT, 42.4 ± 4.2 versus 34.7 ± 2.6, respectively; p = 0.14; and atropine, 47.8 ± 2.5 versus 52.0 ± 2.1, respectively; p = 0.22). Palpitations were more frequent in patients at baseline (55 versus 0 %, p = 0.006) and with VM (82 versus 10 %, p = 0.001) and HUT (64 versus 0 %, p = 0.002), but not with atropine (64 versus 60 %, respectively; p = 0.86). Patients discriminated more types of palpitations than did controls (seven versus three types). No difference was observed in somatosensory amplification or heartbeat perception. Interpretation Palpitations were independent of tachycardia and were predominantly sympathetically mediated. The lack of somatosensory amplification militated against R. K. Khurana (&) Department of Medicine, MedStar Union Memorial Hospital, 201 East University Parkway, Baltimore, MD 21218, USA e-mail: [email protected]
psychogenicity. PoTS patients were not superior in detecting peripheral cardiac sensation. However, patients were superior in discriminating palpitations qualitatively in response to individual stimuli, suggesting central visceral sensitization. Explanation of the nature of symptoms and pharmacologic management may be of therapeutic benefit. Keywords Postural tachycardia syndrome Tilt-table test Valsalva maneuver
Introduction Postural tachycardia syndrome (PoTS) is recognized as a constellation of predominantly orthostatic symptoms including dizziness, palpitations, shortness of breath, chest pain, anxiety, and fatigue [2, 17]. Multiplicity and severity of symptoms and significant disability in PoTS exceed demonstrable medical disease, suggesting psychogenicity. This assumption has led to long-standing scientific debate about the biologic nature of PoTS. In 1918, Fraser and Wilson [6] administered intravenous adrenaline in 10 patients with DaCosta’s syndrome (an alternative name for PoTS) and four control subjects. Control subjects developed only transient pallor of the face. Four of ten patients manifested no symptom after receiving normal saline. With administration of adrenaline, all 10 patients developed pallor of face followed by flushing, feeling of generalized warmth, throbbing in the chest and head, and constrictive feeling in the chest, suggesting organicity of PoTS. In a study of a larger cohort of 300 patients in 1941, Wood [25] concluded that DaCosta’s syndrome should be regarded as an emotional reaction of psychoneurotic subjects. BenrudLarson and colleagues [3] attributed significant disability in PoTS to catastrophic cognitions, somatic vigilance, and
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anxiety sensitivity. This diagnostic dilemma can lead to inappropriate diagnosis and treatment of this debilitating condition. PoTS is a syndrome with inherent heterogeneity, disabling symptoms, and no single confirmed etiology [9]. Therefore, we studied palpitations, a common symptom of PoTS. Palpitations are experienced by up to 89 % of patients with PoTS [22, 25]. Palpitation, a sensory symptom, is broadly defined as an unpleasant awareness of the heartbeat. Palpitations are experienced in a variety of ways, from fluttering to pounding, under physiologic or pathologic conditions. Physiologic conditions include exercise, emotional reaction, stress, and consumption of nicotine or caffeine. Pathologic disorders associated with palpitations are cocaine and ephedrine use, anemia, hyperthyroidism, hypoglycemia, pheochromocytoma, and cardiac disorders of rhythm, rate, and contractility [4]. Palpitation is a complex bodily sensation involving visceral, somatic, cognitive, and affective components. Heartbeat, a marker for palpitations, although not as complex, can be measured precisely and easily. We used heartbeat as a measure of visceral perception to dissect the psychologic versus organic nature of symptoms in PoTS. We hypothesized that palpitations in PoTS are heart rate dependent and that patients amplify their visceral sensations. We also hypothesized that patients have superior heartbeat perception ability. Heart rate was altered quantitatively and qualitatively with two physiological stimuli [Valsalva maneuver (VM) and head-up tilt] and one pharmacological stimulus with atropinization to compare effect on palpitations in patients and healthy controls. With simple validated measures, we compared somatovisceral amplification using a scale of somatosensory amplification and cardiac perception accuracy using a heartbeat perception test.
system such as diabetes mellitus, cardiovascular disease, or cardiac arrhythmias. Hematologic screening; renal, liver, thyroid, and adrenal tests; sedimentation rate; serum protein electrophoresis; vitamin B12 levels; hemoglobin A1c; and urinary porphyrin determination were normal. Electrocardiography, echocardiography and 24-h Holter monitoring were normal in all patients. All patients had undergone cardiovagal, adrenergic, and sudomotor tests to document the diagnosis of PoTS. Control subjects were not taking any medication. PoTS patients were off all medications for 7 days. All participants were instructed to fast overnight and to avoid analgesics, caffeine, nicotine, and exercise on the day of testing. The participants were studied in the morning after a light breakfast. They lay supine in a room at 22 °C with head elevated comfortably at a 15° angle. They were familiarized with the equipment and the nature of the procedures. Blood pressure and heart rate were monitored noninvasively with a beat-to-beat blood pressure plethysmograph (Finapres, Ohmeda 2300) and heart rate monitor, respectively. An intravenous line was started in the antecubital vein with the use of a 19-gauge needle and heparin lock solution. The testing was completed in a 2-h session. Somatosensory amplification scale The somatosensory amplification scale (SSAS) was used to study self-reported sensitivity to normal somatic and visceral sensation. The participants used a five-point scale to rate the degree of discomfort associated with 10 ‘‘benign’’ sensations. This test quantifies the intensity of various symptoms and does not involve the subjective judgment of a physician. The test–retest reliability and internal consistency of SSAS have been demonstrated [1]. Each participant’s rating of each of the 10 items were added to obtain a somatosensory amplification score. A higher score indicated greater symptom amplification.
Methods Heartbeat perception test Participants The Institutional Review Board approved the study and all participants gave informed consent. Ten control subjects and 11 PoTS patients participated in the study. No controls had history of systemic disease, mitral valve prolapse, cardiac arrhythmia, vasovagal syncope, psychiatric disease, or pregnancy. All PoTS patients fulfilled the diagnostic criteria including symptoms of orthostatic intolerance, [6 months history, orthostatic tachycardia C30 bpm in response to 10 min of head-up tilt (HUT) or an absolute heart rate [120 bpm without orthostatic hypotension. Patients had no past history of panic disorder or of any systemic illness likely to affect the autonomic nervous
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The heartbeat perception test (HBPT) is a standard noninvasive measure of interoceptive awareness. It is a mental tracking paradigm developed by Schandry [23] to assess an individual’s objective ability to detect the heartbeat. Subjects, in supine position, were asked to take off their watch, to not count their pulse or hold their breath, and to look at the blank wall to the left. The finger cuff of the Finapres blood pressure instrument was removed. A start and stop signal between the investigator and the participant was established before starting timed trials. Before the test, a familiarization task was administered for 12 s. Participants were unaware of the length of the counting phases. The participants silently counted the heartbeats they felt in their
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body during signaled intervals of 35, 25, and 45 s with 30-s intervals between each phase. After each trial, the subjects reported the number of counted heartbeats. No performance feedback regarding degree of accuracy was provided. Actual heart rate data were derived from counts of the number of R waves in each segment of the electrocardiogram. Both counted and actual heartbeat responses were recorded. HBPT was quantified as an error score (inaccuracy). Degree of inaccuracy was calculated as the difference between reported and actual number of heartbeats divided by the actual number of heartbeats and multiplied by 100. The result was expressed as a percentage error score. Mean error score was derived by averaging the results of three trials. Symptom stimulation The symptom of palpitations was recorded at rest and in response to physiologic and pharmacologic stimuli. Participants were asked to select the type of palpitation from one of eight previously identified varieties: pounding, thumping, heart beating in the neck, racing, skipping, stopping, fluttering, and heart beating irregularly [24]. Participants rated palpitation severity on a visual analog scale of 1–10. Palpitation severity was classified arbitrarily based on the severity scale as mild, 1–3; moderate, 4–7; and severe, 8–10. Two sympathoexcitatory physiologic stimuli were used: the VM and the HUT. The VM was performed with the subject in supine position. The participant initiated the maneuver at the end of normal inspiration, raised expiratory pressure quickly to 40 mmHg, and maintained it for 15 s [13]. In the HUT, the participant was loosely strapped across chest and thighs to an electrically operated table with foot support. Baseline measurements of blood pressure and heart rate were obtained for 5 min before the table was tilted upright to 90° and maintained for 10 min [14]. Atropine was used for pharmacologic vagolysis to increase the heart rate. An intravenous bolus of atropine, 0.03 mg/kg body weight, was administered and heart rate was continuously monitored [12]. The peak (not steady state) heart rate rise, over the 30-s average baseline, in response to various stimuli was compared between control subjects and patients.
and HBPT for 45 s then rest for 3 min. VM was administered, and the investigator asked about palpitations immediately after cessation of expiratory strain. The individual rested for 3 min. HUT was administered for 10 min, during which the individual enumerated all symptoms as they occurred, including palpitations, followed by rest for 10 min. Atropine was then administered, and the investigator asked about palpitations during this test and observed until heart rate began to decline. Statistical analysis The number of study subjects was ascertained by power analysis, which found that 10 subjects in each group would be adequate to detect an increase in heart rate of at least 20 beats per minute with a power of 80 % at the 0.05 probability level assuming a standard deviation of 20 beats per minute. Data were compared using an unpaired two-sided t test and one-way ANOVA. Statistical analysis was done using Statgraphics.
Results The mean age of control subjects was 27.6 ± 4.4 (mean ± SD) years and 8 of 10 (80 %) were female. The mean age of PoTS patients was 31.9 ± 9.4 (mean ± SD) years and 8 of 11 (73 %) were female. Baseline HR was significantly higher in PoTS patients than in healthy control subjects (79 ± 2 versus 70 ± 2 bpm, p \ 0.01). Differences in heart rate increase in response to three stimuli were not statistically significant (Table 1). PoTS patients had significantly greater occurrence of palpitations compared with control subjects at baseline (55 versus 0 %, p = 0.006), after VM (82 versus 10 %, p = 0.001), and after HUT (64 versus 0 %, p = 0.002). No difference in occurrence of palpitations was observed after atropine administration (patients, 64 %; control subjects, 60 %; p = 0.86) (Tables 2 and 3). Symptom severity was higher in patients than in control subjects. At baseline, control subjects had no palpitations, whereas palpitations of PoTS patients were moderate to severe (severity, 4–8). In Table 1 Peak heart rate increase in response to stimuli
Experimental design
Test
Heart rate increase (bpm) (mean ± SE) Control subjects
Instrumentation was done, followed by instruction and trials of 12-s HBPT and 15-s VM. The individual rested for 15 min. The investigator asked about palpitations at rest and then administered the somatosensory amplification scale, followed by rest for 5 min. HBPT was administered for 25 s then rest for 30 s, HBPT for 35 s then rest 30 s,
p value
Patients
VM
28.9 ± 3.9
39.3 ± 4.7
0.11
HUT Atropine
34.7 ± 2.6 52.0 ± 2.1
42.4 ± 4.2 47.8 ± 2.5
0.14 0.22
Bpm Beats per minute, SE standard error, VM Valsalva maneuver, HUT head-up tilt
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Clin Auton Res Table 2 Palpitations: control subjects No.
Baseline
VM
Grade
HUT
Atropine
Grade
1
No
No
–
No
Racing
3
2
No
No
–
No
No
–
3
No
No
–
No
Racing
8
4
No
No
–
No
Racing
4
5
No
No
–
No
No
–
6
No
No
–
No
No
–
7
No
No
–
No
2
8
No
No
–
No
Heart beating in neck No
9
No
Thumping
2
No
Racing
4
10
No
No
–
No
Racing
4
–
that questions pertaining to pollutants and prolonged bruising elicited significantly elevated responses in PoTS patients. No difference between groups was observed in response to questions pertaining to autonomic dysfunction such as ambient temperature tolerance and hunger contractions. The ability of control subjects to detect their heartbeat was variable with error scores ranging from 1.4 to 40.4 %. Error scores in PoTS patients were distributed over an extremely wide range, from 3 to 104 %. No statistically significant difference in percentage error scores between groups was found [control subjects, 14.4 ± 3.5 (mean ± SE); patients, 25.2 ± 9.8; p = 0.31].
VM Valsalva maneuver, HUT head-up tilt, – not applicable
Discussion response to VM and HUT, control subjects had no or mild palpitations whereas most PoTS patients had mild to severe palpitations. Atropine produced mild to severe (severity, 2–8) palpitations in both control subjects and PoTS patients. Control subjects discriminated three different types of palpitations (5 racing, 1 heart beating in neck, and 1 thumping) (Table 2). Patients discriminated seven different types of palpitations (12 racing, 8 pounding, 3 heart beating in neck, 3 fluttering, 2 thumping, 1 skipping, and 1 irregular heartbeat) (Table 3). PoTS patients also appeared to discriminate different types of palpitations with different stimuli (Table 3). Cardiac rhythm was normal during the study. There was no difference in overall somatosensory amplification between normal subjects and controls [14.4 ± 2.3 (mean ± SE) versus 17.5 ± 1.5, respectively; p = 0.27]. Analysis of individual items (Table 4) showed Table 3 Palpitations: PoTS patients
VM Valsalva maneuver, HUT head-up tilt, – not applicable
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No.
Baseline
1
Skipping
2
Racing
3 4
No Racing
5 6
Grade
The current data show that palpitations in PoTS are of organic origin. PoTS patients and control subjects did not differ in palpitation response to atropine-induced tachycardia, but PoTS patients had significantly more palpitations compared with healthy controls in response to the Valsalva maneuver and head-up tilt, two stimuli that cause sympathetic excitation. These findings, along with the lack of statistically significant difference in peak heart rate response between the groups, suggest that palpitations in PoTS are mediated predominantly by sympathoexcitatory stimuli and are independent of tachycardia. PoTS patients did not amplify their somatic and visceral sensations compared with control subjects, indicating that they are not predisposed to exaggerating every symptom and militating against psychologic origin. PoTS patients also did not display superior ability to perceive heartbeat, suggesting normal peripheral visceral input. However, patients had greater ability to discriminate the type of palpitation
VM
Grade
HUT
Grade
Atropine
Grade
4
Thumping
10
No
–
Racing
7
6
Fluttering
2
Irregular heartbeat
5
No
–
– 6
Pounding Pounding
6 9
Racing No
6 –
No No
– –
Racing
4
No
–
No
–
Racing
2
Racing
8
Pounding
6
Pounding
3
Heart beating in neck
6
7
No
–
Pounding
6
Racing
8
Racing
5
8
Fluttering
8
Pounding
7
Racing
8
Heart beating in neck
8
9
No
–
No
–
No
–
Fluttering
4
10
No
–
Racing
3
Racing
5
Pounding
5
11
No
–
Thumping
6
Pounding
4
Heart beating in neck
7
Clin Auton Res Table 4 Response (mean ± SE)
to
Question
somatosensory Control subjects (n = 10)
amplification Patients (n = 11)
scale p value
When someone coughs, it makes me cough too
0.20 ± 0.13
0.27 ± 0.14
0.71
I cannot stand smoke, smog, or pollutants in the air I am often aware of various things happening within my body
1.40 ± 0.31
2.70 ± 0.47
0.03
2.20 ± 0.44
2.36 ± 0.24
0.74
When I bruise myself, it stays noticeable for a long time
1.40 ± 0.34
2.64 ± 0.34
0.02
Sudden loud noises really bother me
1.50 ± 0.40
1.91 ± 0.34
0.45
I can sometimes hear my pulse or my heartbeat throbbing in my ear
1.10 ± 0.28
2.00 ± 0.38
0.08
I hate to be too hot or too cold
2.40 ± 0.43
1.54 ± 0.25
0.33
I am quick to sense the hunger contractions in my stomach
2.40 ± 0.43
1.54 ± 0.25
0.09
Even something minor like an insect bite or a splinter really bothers me
0.90 ± 0.34
0.36 ± 0.20
0.19
I have a low tolerance for pain
0.90 ± 0.43
0.72 ± 0.27
0.73
14.40 ± 2.33
17.45 ± 1.49
0.27
Total
compared with control subjects, favoring visceral hypersensitivity and a central origin of PoTS symptoms. PoTS patients share several symptoms with panic disorder and anxiety including palpitations, dizziness, chest pain, shortness of breath, and tremulousness. Benrud-Larson and colleagues assigned a significant role to catastrophic cognitions, somatic vigilance, and anxiety sensitivity in causing disability in PoTS [3]. Another study using the Acute Panic Inventory (API), a validated 17-item scale to assess severity of panic symptoms, demonstrated significantly elevated scores in PoTS patients (26.32 ± 2.34 SE) compared with normal subjects (0.8 ± 0.28.SE) [11]. However, attempts to provide further scientific confirmation of a ‘‘psychological’’ disorder beyond validated questionnaires have yielded negative results. For example, in one study [10], 11 patients and 11 control subjects were subjected to three panic provoking stimuli: 10-min head-up tilt, isoproterenol infusion, and 0.5 M racemic sodium lactate infusion. Sodium lactate, an established experimental precipitant of panic in patients with panic disorder, failed to produce panic symptoms in
PoTS. None of the stimuli produced increased API scores in the cognitive psychological domain essential to the diagnosis of panic disorder, such as fear of dying, fear in general, sense of unreality, and feeling detached. Masuki et al. [16]. found no correlation between lower body negative pressure-induced tachycardia and the psychological variables of anxiety sensitivity, somatic vigilance, and catastrophic cognitions, indicating that anxiety is not the primary cause for the excessive orthostatic tachycardia. Using the Beck Anxiety Inventory and the Anxiety Sensitivity Index, Raj and colleagues [21] showed that patients were moderately anxious but did not exhibit a high level of anxiety sensitivity. The authors found no significant correlation of supine, upright, or change in norepinephrine with the Beck Anxiety Inventory. The cited data, the lack of somatosensory amplification demonstrated in the current study, and the absence of reported improvement or amelioration of the syndrome with isolated psychological management fail to support the psychologic origin of palpitations. Palpitations in PoTS are mediated predominantly by sympathetic excitation independently of tachycardia. This interpretation is supported by the lack of difference between the groups in palpitation frequency and severity after chemical vagolysis, the observation that only one control subject felt palpitations in response to VM or HUT, and the significantly higher incidence of palpitations in patients with VM and with HUT despite the lack of statistical difference in peak heart rate increase between the groups. A study by Raj and colleagues showing a significant decrease in palpitations with beta adrenoreceptor blockade also supports this contention [20]. Sympathetic excitation is likely to be of cerebral origin. Functional magnetic resonance imaging during VM recruits central autonomic pathways, which are critical for interoceptive awareness, including the hippocampus, amygdala, brainstem, and insular and lateral frontal cortices [8]. Moreover, peripherally released catecholamines are generally unable to penetrate the developed blood–brain barrier [15]. The lack of difference between groups in degree of inaccuracy at heartbeat perception in the current study suggests a similar peripheral input. Almost all patients discriminated palpitations by type compared with one control subject despite identical stimuli. This ability to discriminate the quality of palpitations in response to individual stimuli favors altered central processing and visceral hypersensitivity. Potential locations for visceral hypersensitivity include sensory receptors in the cardiovascular system, extrinsic sensory afferent neurons, spinal nociceptive neurons, medulla, midbrain raphe, hypothalamus, and cortex [2, 5, 19]. In the current study, palpitations were differentially observed in PoTS patients during sympathetic stimulation, whereas the effects of vagolytic
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stimulus were similar to those observed in control subjects. Such differential effects depending on the mode of induction of tachycardia argue against sensitization of spinal neurons, which should have responded identically to both types of tachycardia. Therefore, higher levels of the neuraxis (e.g., insular cortex [2, 18]) or multilevel involvement is the most likely explanation. Although visceral sensitization can be maintained by tonic impulse input from the heart and by facilitation from the brain to spinal cord (enhanced afferent processing [19]), the visceral responses cannot be elaborated into a discriminatory component solely through peripheral action. For discrimination of visceral response, the neocortex must work conjointly with the insular cortex and the hippocampus [7]. PoTS is a heterogeneous disorder [9], and the concept of visceral sensitization may not apply to every subset of PoTS. Palpitations did not occur in all patients in this study. The data were partly dependent on answers to indirect measures. One cannot be sure that during HBPT, the subjects were not guessing their average heart rate without actually attending to the heartbeats. Because of the limited number of PoTS patients available for study, the study had power to detect only relatively large differences. A study with objective correlates such as fMRI in a larger number of patients would provide more information. Visceral sensitization helps to explain (1) the phenotype of PoTS despite the underlying heterogeneity of multiple etiologies, (2) a poor correlation between the severity of symptoms and the extent of hemodynamic parameters, (3) multiple and severe symptoms lacking objective correlation, and (4) persistence of orthostatic symptoms despite adequate control of heart rate. PoTS patients should be reassured that unusual visceral sensations (such as feeling pulsations in fingertips or eyeballs) are caused by visceral hypersensitivity and that sympathetic stimuli may precipitate or aggravate palpitations. The current study suggests that drugs that enhance central inhibition or reduce excitation may be useful in ameliorating PoTS symptoms. Acknowledgments I thank Norman Dubin, PhD., for statistical analysis and Lyn Camire, MA, ELS, for editorial assistance. Conflict of interest
The author reports no conflict of interest.
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