There is a subgroup of individuals with neurocardiogenic hypotension and bradycardia who have a milder form of orthostatic intolerance, and may present complaints of orthostatic light headedness, postural tachycardia, disabling fatigue, exercise intolerance, and dizziness, or near syncope (1,2). These patients show a less dramatic orthostatic fall in blood pressure that is insufficient to cause full syncope, but may produce postural orthostatic tachycardia and the presented symptoms. Grubb et al. (1) reported that these patients, who have postural orthostatic tachycardia syndrome (POTS), exhibit an exaggerated response to isoproterenol infusion and can be readily diagnosed by the head-up tilt table test. In the present study, we compared the heart rate and plasma cyclic AMP (cAMP) responses to isoproterenol infusion in the supine position between POTS patients and control subjects, and investigated the effectiveness of beta-blocker therapy for POTS patients using the head-up tilt testing.
The subjects were 10 POTS patients who complained of palpitations, exercise intolerance, dizziness, fatigue, and near syncope. Patients who suffered from complete syncope were excluded. Patients who were on chronic antihypertensive, diuretic, anticholinergic, or antidepressant medication were also excluded. A thorough history was taken and a complete physical examination was carried out in each patient, as well as detailed biochemistry tests and a thyroid hormone profile. The head-up tilt test (80° for 15 min) was performed in the fasting state. The standard electrocardiogram was monitored for continuous evaluation of heart rate, and the blood pressure was measured every 20 s using an automatic blood pressure cuff. A positive test was defined by reproduction of the patient's symptom complex. Ten age-matched control subjects were also tested in the same manner. POTS was defined using the following criteria; a heart rate increase of > 30/min (or a maximum heart rate of 120/min) within 10 min of starting the test (unassociated with profound hypotension), plus reproduction of the symptom complex during the head-up tilt test.
This study was conducted with two protocols. The first protocol involved measurement of the responses of the heart rate and the plasma cAMP concentration to a low dose (1 μg/min) of isoproterenol infused intravenously in the supine position in the 10 POTS patients and 10 controls. Blood samples to measure the plasma cAMP level were drawn from the cubital vein into tubes containing ethylenediamine tetra-acetic acid before and 10 min after the start of isoproterenol infusion. The blood was centrifuged to obtain the plasma. The cAMP level was determined using a radioimmunoassay Kit (Yamasa, Chiba, Japan) after succinylation of the sample, with measurement being carried out according to the method of Honma et al. (3). In the second protocol, the effects of oral beta-blocker therapy were assessed in seven out of 10 POTS patients using head-up tilt table testing.
Among the 10 POTS patients evaluated, there were two men and eight women. The mean age was 19.7 years, ranging from 15 to 28 years. All patients showed normal laboratory parameters as well as normal thyroid function. The symptoms of POTS included orthostatic tachycardia in eight patients, fatigue in five, vertigo or dizziness in four, and exercise intolerance in six patients. The heart rate response to head-up tilt testing is shown in Fig. 1. In the supine position, the heart rate did not differ between the POTS patients and the control subjects. However, the heart rate during upright tilting increased significantly in the POTS patients when compared with that in control subjects. This significant increase of heart rate persisted until a return to the supine position during head-up tilt testing. Systolic and diastolic blood pressure during head-up tilt testing did not differ between the POTS patients and the controls.
Heart rate and plasma cyclic AMP responses to isoproterenol infusion (Fig. 2)
The heart rate response to the infusion of isoproterenol in the supine position is shown in Fig. 2A. The heart rate increased significantly from 60 ± 7/min before infusion of isoproterenol to 122 ± 11/min after 10 min of isoproterenol infusion in seven POTS patients, and from 60 ± 4/min to 94 ± 9/min in the 10 control subjects. Although there was no significant difference in heart rate between the POTS patients and the controls before the administration of isoproterenol, the heart rate after 10 min of isoproterenol infusion was significantly higher in POTS patients than in control subjects (p < 0.01).
The plasma cAMP concentration before and after 10 min of isoproterenol infusion in the supine position is shown in Fig. 2B. The cAMP concentration increased significantly from 13.5 ± 2.3 pmol/ml before the infusion of isoproterenol to 27.0 ± 3.3 pmol/ml after isoproterenol infusion in the POTS patients, and from 14 ± 1.6 pmol/ml to 19.4 ± 2.4 pmol/ml in the control subjects. Although there was no significant difference in the cAMP concentrations before isoproterenol administration, the POTS patients had significantly higher cAMP levels than the control subjects after the infusion of isoproterenol (p < 0.05).
Effect of beta-adrenergic blockade in POTS patients
In seven out of 10 POTS patients, oral beta-blocker therapy was initiated and its effect was evaluated by the head-up tilt table test. Oral propranolol at a dose of 30 mg/day (three times daily) was administered to six patients and oral atenolol at a dose of 25 mg/day was administered to one patient. Beta-blocker therapy abolished symptoms and reduced the heart rate increase during head-up tilt test in five of the seven POTS patients. In the remaining two patients, the heart rate increase during head-up tilt test was only slightly different to that before therapy. In these two patients, symptoms persisted during head-up tilt testing.
Transient episodes of neurocardiogenic hypotension and bradycardia are a well-recognized cause of recurrent syncope and near syncope. Tilt table testing is a reliable method for provoking episodes of autonomic decompensation and has not only proven to be a useful diagnostic tool, but has also led to much better understanding of the pathophysiology of these disorders (4-6). In the course of these investigations, Grubb and coworkers (1,6) and Jacob et al. (7) have identified a large subgroup of patients who appear to have a less severe form of orthostatic intolerance that is characterized by postural tachycardia, exercise intolerance, disabling fatigue, light headedness, and dizziness. This disorder has generally become known as POTS. It appears that POTS may be more prevalent in young women. In fact, the mean age of our POTS patients in the present study was 19.7 years old, ranging from 15 to 28 years, and eight of the 10 patients were women (1,8,9). During the head-up tilt test, these patients displayed an exaggerated heart rate increase of more than 30/min within 10 min of adopting the upright position. While this increase of heart rate was not usually associated with significant hypotension, it accurately reproduced the patient's symptoms. This response was not observed in our normal control subjects during the head-up tilt test (9). However, the details of this syndrome have not been clear, especially its pathophysiological mechanism and treatment.
In the present study, we found that POTS patients showed exaggerated responses of the heart rate and plasma cAMP concentration during low-dose isoproterenol infusion when compared with the control subjects. Also, the heart rate of the POTS patients in the upright posture was significantly higher than that of control subjects. These results suggest to us that hypersensitivity of adrenergic receptors in these patients might be involved in the mechanism of POTS, as described by Jacob et al. (7). In fact, oral beta-blocker therapy was useful for controlling the POTS symptoms and for lessening the heart rate increase during head-up tilt test in five out of seven POTS patients. However, the remaining two patients did not experience complete relief of their symptoms with beta-blocker therapy. Therefore, other mechanisms may also be involved in this disorder. A larger series of patients needs to undergo further studies in the future to resolve these issues.
In the present study, we evaluated 10 patients who were diagnosed as having postural orthostatic tachycardia syndrome by head-up tilt test. Eight of the 10 patients were women, and their mean age was 19.7 years (range, 15-28 years). Exaggerated heart rate and plasma cAMP responses to a low dose of isoproterenol were observed in these patients during testing, but were not observed in normal control subjects. In five out of seven POTS patients, beta-blocker therapy was effective in controlling their symptoms and in reducing the heart rate response during head-up tilt test. Adrenergic hypersensitivity may be involved in the mechanism of this disorder.
Acknowledgement: This study was supported by a Project Research Grant from The University of Occupational and Environmental Health, Japan.
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The symposium and the publication of this supplement were supported by an educational grant from Novartis Pharma K.K. Tokyo, Japan.