Abnormal Forearm Vascular Responses During Dynamic Leg Exercise in Patients With Vasovagal Syncope
Background We have reported previously that in some patients with normal hearts who present with exercise syncope, abnormal forearm vasodilation is seen during leg exercise and tilt table tests are positive. This suggests that exercise syncope may be a variant of vasovagal syncope. In this study we tested the hypothesis that there is loss of the normal forearm vasoconstrictor response during dynamic leg exercise in an unselected population of patients with classic vasovagal syncope.
Methods and Results We evaluated forearm vascular responses during maximal semierect cycle exercise in 28 consecutive patients with vasovagal syncope and compared them with 30 age-matched control subjects. We also evaluated blood pressure responses during erect treadmill exercise (Bruce protocol). While forearm vascular resistance at rest was similar in the patients with vasovagal syncope and the control group, forearm vascular resistance was markedly lower in the patients than in control subjects at peak exercise (85±54 versus 149±94 units, P=.002). Forearm vascular resistance fell by 3±48% during exercise in patients versus an increase of 135±103% in control subjects (P<.0001). Systolic blood pressure during erect exercise was lower in patients versus control subjects (155±32 versus 188±17 mm Hg, P<.0001). Six of the vasovagal patients complained of exercise syncope or presyncope on specific inquiry, and 4 of these 6 exhibited exercise hypotension during erect treadmill exercise testing.
Conclusions Patients with vasovagal syncope exhibit a failure of the normal vasoconstrictor response in the forearm during dynamic leg exercise. Exercise syncope and presyncope are not uncommon in unselected patients with classic vasovagal syncope, as is exercise hypotension.
Vasovagal syncope is a common disorder that has attracted renewed interest over the past decade with the widespread introduction of tilt table testing.1 Common precipitants include prolonged standing, emotion, and pain. Activation of left ventricular mechanoreceptors in the setting of an underfilled hypercontractile ventricle has been proposed as a mechanism of the vasovagal response,2 but recent evidence calls the central role of this mechanism into question, at least in some patients.3 4 Activation of other cardiopulmonary mechanoreceptors in the atria or great veins may play a role.5 Recently we have reported a small series of otherwise healthy adults with exercise syncope in whom exercise hypotension was associated with abnormal vasodilation in nonexercising vascular beds.6 All subjects also developed vasovagal responses during tilt testing. Another recent study reported vasovagal responses during tilt table testing in 19 of 24 otherwise healthy young adults presenting with exercise syncope.7 This suggests that exercise syncope in otherwise healthy young subjects frequently may be a variant of vasovagal syncope. We hypothesized that a failure of the normal forearm vasoconstrictor response during dynamic leg exercise may be common in patients with vasovagal syncope, reflecting probable enhanced cardiopulmonary mechanoreceptor activation during exercise.
Fifty-eight patients were referred to the Syncope Clinic of the Royal Brisbane Hospital between January 1993 and August 1994 for assessment of syncope. A diagnosis of vasovagal syncope was established in 28 patients (age, 17 to 68 years; mean, 41.6 years; 11 men and 17 women) on the basis of a typical history, negative EEG, echocardiography, and cardiac electrophysiological study where appropriate, and a positive head-up tilt test without isoproterenol.8 None of the patients had a history suggestive of ischemic heart disease, none was hypertensive, all had negative exercise ECGs for ischemia, and all were in sinus rhythm. None had evidence of autonomic failure or orthostatic hypotension on formal testing.9 Thirty approximately age-matched normal subjects (age, 18 to 69 years; mean, 44.3 years; 22 men and 8 women) with no previous cardiac history or current symptoms, normal cardiovascular and neurological examination, normal ECG and echocardiogram, and negative tilt test were enrolled as control subjects. The normal subjects were recruited from the gastroenterology department database. The patients and the control subjects were sedentary. There were no differences in the degree of physical activity engaged in by patients or control subjects.
The investigations were performed at the Royal Brisbane Hospital with the approval of the hospital ethics committee. Informed consent was obtained from all patients and control subjects. Subjects arrived at 8 am, fasting from midnight on 2 consecutive days. Forearm blood flow was measured during semierect cycle exercise on the first day and blood pressure responses during erect treadmill exercise on the second day. All cardioactive medications were withdrawn for at least 5 half-lives before the study.
Exercise Forearm Vascular Responses
Patients were studied in a quiet environment at a constant room temperature of between 22° and 24°C. Forearm blood flow was measured using a standard mercury-in-Silastic strain gauge plethysmography technique (Hokanson).10 Standard surface ECG and forearm blood flow recordings were fed to the Acq Knowledge multichannel data acquisition system (Biopac Systems). Blood pressure was measured with the use of a mercury sphygmomanometer. After measurements were made at rest, patients performed symptom-limited semierect cycle exercise commencing at 25 W and increasing by 25 W every 3 minutes to symptom-limited maximum, and forearm blood flow was measured during the final minute of each stage and at maximal exercise. Forearm blood flow at each stage was calculated from the mean of three slopes. Forearm vascular resistance, expressed in resistance units, was calculated as the quotient of the mean arterial pressure (mm Hg) and forearm blood flow (mL/min per 100 mL).
Erect Exercise Blood Pressure Responses
Maximal symptom-limited treadmill exercise testing was performed the following day with use of the Bruce protocol. Systolic blood pressure was measured by a single operator using digital palpation of the brachial artery with the use of a mercury sphygmomanometer at rest and at 1-minute intervals during exercise. A hypotensive response during exercise was defined by one of the following patterns11 : (1) peak blood pressure<rest blood pressure or (2) initial rise in blood pressure on exercise but a subsequent fall of BP at peak exercise by 20 mm Hg.
We elected to use digital palpation to measure blood pressure rather than an invasive method because of concern that instrumentation could induce a vasovagal response resulting in hypotension. Our group has had extensive experience with this technique in patients with hypertrophic cardiomyopathy. We have demonstrated previously that the pattern of blood pressure response (ie, hypotensive or normal) identified by palpation of the brachial artery is validated by intra-arterial recordings.12
Response to Handgrip and Intravenous Phenylephrine
To assess whether the vasoconstrictor response to α-adrenergic stimulation is impaired in patients with vasovagal syncope, we assessed the blood pressure response to the α1-agonist phenylephrine in patients and control subjects. In brief, phenylephrine was injected into an antecubital vein. Blood pressure was measured with the use of a Finapress recorder (Ohmeda 2300). Blood pressure and ECG data were recorded using the acq knowledge data acquisition program on an Apple McIntosh IICI computer. The dose required to produce an increase in systolic blood pressure of approximately 30 mm Hg was divided by the patient’s weight to give a weight-adjusted dose-response ratio.
To assess whether reflex responses to other pressor maneuvers were impaired in patients with vasovagal syncope, the response of diastolic blood pressure to handgrip was assessed in patients and control subjects. Handgrip was maintained at 30% of the maximum voluntary contraction up to a maximum of 5 minutes with use of a handgrip dynamometer, and blood pressure was measured each minute. The difference between the blood pressure just before release of handgrip and before starting was taken as the measure of response.
Data are expressed as mean±SD. Statistical analysis was performed with use of the Student’s paired and unpaired t tests and by the χ2 test where appropriate. A probability value of <.05 was considered significant.
The patients and control subjects were reasonably matched for age (41.6±16.7 versus 44.3±16.5 years, respectively). There were disproportionately more men in the control group (22 of 30) versus the patient group (13 of 28). The patients had experienced 9.3±6.7 prior episodes of syncope (versus none in the control subjects). On direct inquiry, 6 of the 28 patients complained of exercise presyncope versus none of the control subjects.
Exercise Forearm Blood Flows
As shown in Table 1⇓, resting heart rate, systolic blood pressure, forearm blood flow, and forearm vascular resistance were similar in patients and control subjects, as was heart rate at peak exercise. During semierect cycle exercise, peak systolic blood pressure was lower in patients versus control subjects (115±17 versus 128±22 mm Hg, P=.02), forearm blood flow was higher in patients versus control subjects (2.2±1.6 versus 1.1±0.6 mL/100 mL per minute, P=.002), and forearm vascular resistance was lower in patients versus control subjects (85±54 versus 149±94 units, P=.002). Forearm vascular resistance fell by 3±48% during exercise in patients versus an increase of 135±103% in control subjects (P<.0001) (Fig 1⇓). In 19 of 28 patients, a fall in forearm vascular resistance was observed during exercise, a pattern that was seen in only 1 of 30 control subjects. In the patient group, three patterns of response of forearm vascular resistance to exercise were seen. Nine patients behaved in a similar fashion to control subjects, with forearm vascular resistance increasing with each stage of exercise (Fig 2⇓). Of the patients in whom there was a paradoxical fall in peak forearm vascular resistance on exercise, 13 demonstrated a progressive fall in forearm vascular resistance at each stage of exercise (Fig 3⇓). In 6 patients, forearm vascular resistance initially increased and then fell with progressive exercise (Fig 4⇓).
The duration of exercise was not significantly different in the two groups (727±226 seconds in patients versus 853±352 seconds in control subjects, P=NS). The workload achieved also was similar in the two groups (93±32 W in patients versus 108±47 W in control subjects, P=NS).
As shown in Table 2⇓, age, frequency of episodes of vasovagal syncope, and the frequency of a history of exercise syncope were similar in those with normal exercise vascular responses and those with abnormal vascular responses. After excluding the 6 patients with a history of exercise syncope or presyncope, the percent change in forearm vascular resistance during exercise was still lower in patients versus control subjects (+5±48% versus +135±103%, P<.0001).
Erect Exercise Blood Pressure Responses
As shown in Table 3⇓, resting and peak heart rates were similar in patients and control subjects. Systolic blood pressure was similar at rest in patients and control subjects but was lower at peak exercise in patients versus control subjects (155±32 versus 188±17 mm Hg, P<.0001). Exercise hypotension was observed in 4 patients but in none of the control subjects. Exercise hypotension was observed in 4 of 6 patients with a history of exercise syncope versus 0 of 22 without a history of exercise syncope (P<.0001). Exercise duration was similar in patients and control subjects (617±196 seconds versus 650±191 seconds, P=NS), which corresponded to a workload of 13±4 mets in patients versus 14±4 mets in control subjects (P=NS).
Response to Handgrip and Phenylephrine
The increase in diastolic blood pressure during handgrip was similar in the patients and control subjects (23±10 versus 22±10 mm Hg, P=NS). The phenylephrine dose-response ratio also was similar in the patients and control subjects (3.9±2.3 versus 4.2±2.2 mm Hg/kg per mg phenylephrine, P=NS).
The important findings of this study are that exercise syncope or presyncope is not infrequent in a consecutive series of patients with vasovagal syncope when specifically inquired for (24%), and exercise hypotension is not uncommon (16%). In addition, during dynamic leg exercise, patients with vasovagal syncope exhibit a failure of the normal forearm vasoconstrictor response, and indeed, paradoxical vasodilation was seen in 19 of the 28 patients. The pressor response to α1-adrenergic stimulation and to handgrip is normal in patients with vasovagal syncope.
Physiological Vascular Responses to Dynamic Leg Exercise
Dynamic leg exercise in normal subjects is associated with complex cardiovascular changes. In untrained subjects, cardiac output increases by 3- to 4-fold as a result of a large increase in heart rate and a small increase in stroke volume.13 14 Systemic vascular resistance falls by 2- to 2.5-fold as a consequence of two opposing vascular responses. Profound vasodilation occurs in exercising vascular beds as a result of a local vasodilatory effect of the products of skeletal muscle metabolism.13 Vasoconstriction occurs in nonexercising vascular beds as a result of a complex interplay of cardiovascular reflexes.15 16 17 18 A cortical reflex known as the central command reflex is partly responsible.16 17 Activation of skeletal muscle metaboreceptors also induces a reflex increase in arteriolar tone in nonexercising vascular beds.15 16 18 It seems likely that in normal subjects, the constrictor influences of the above two reflexes are partially attenuated by the effect of partial activation of left ventricular mechanoreceptors during exercise as a result of increased left ventricular wall stresses.19 20 This hypothesis is supported by the observation of exaggerated forearm and renal vasoconstriction in cardiac transplant recipients, presumably because of cardiac vagal deafferentation.19
Abnormal Vascular Responses in Patients With Vasovagal Syncope and Relationship to Exercise Hypotension
We have demonstrated previously that an exaggerated fall in systemic vascular resistance in association with impaired vasoconstriction or vasodilation in nonexercising vascular beds is responsible for exercise hypotension in some patients with hypertrophic cardiomyopathy and in ischemic heart disease.21 22 23 Similar findings have been reported in aortic stenosis.24 In this series of patients with vasovagal syncope, the majority exhibited either impaired vasoconstriction or paradoxical vasodilation in the forearm beds, which if reflected in other vascular beds would result in an exaggerated fall in systemic vascular resistance.
As compared with patients with hypertrophic cardiomyopathy and ischemic heart disease, patients with vasovagal syncope have normal hearts and hence an ability to markedly augment cardiac output in the face of a dramatic fall in afterload. This may provide a rationale for the observation that the minority of patients with abnormal vascular responses developed exercise hypotension. All patients with exercise hypotension exhibited markedly abnormal forearm vascular responses.
Mechanism of Abnormal Vascular Responses
Left ventricular pressure overload in animal studies induces peripheral vasodilation as a result of left ventricular mechanoreceptor activation.25 26 Mark et al24 proposed that profound activation of left ventricular mechanoreceptors may be responsible for exercise syncope in patients with aortic stenosis, and we have proposed a similar mechanism in patients with hypertrophic cardiomyopathy and ischemic heart disease.21 22 23 In these conditions, it is easy to imagine how abnormal regional wall stresses might result in left ventricular mechanoreceptor activation. The patients with vasovagal syncope in this study had no evidence of cardiac disease, and a rationale for enhanced left ventricular mechanoreceptor activation may be less apparent at first sight. A priori, two possibilities exist. First, there may be an intrinsic abnormality of cardiopulmonary mechanoreceptor function in patients with vasovagal syncope. Second, cardiopulmonary mechanoreceptor activation may occur as the result of a sudden fall in cardiac volume on exercise in association with the increased inotropic state associated with exercise. Some authors have reported abnormal control of the venous capacitance system in patients with vasovagal syncope.27 28 A failure of splanchnic venoconstriction on exercise would lead to a small, hypercontractile ventricle. This is a similar scenario, which Almquist et al2 proposed as a mechanism for left ventricular mechanoreceptor activation during tilt table testing.
The hypothesis that vasovagal syncope is due to left ventricular mechanoreceptor activation was based at least in part on the results of rabbit hemorrhage and simulated hemorrhage experiments.29 30 During these experiments, two hemodynamic phases are seen. In phase 1, as cardiac output progressively falls, renal sympathetic nerve activity dramatically increases. When blood volume falls by approximately 30% or cardiac output falls by approximately 50%, there is an abrupt change to phase 2, in which renal sympathetic nerve activity falls again. The observation that phase 2 can be blocked by intrapericardial procaine initially was believed to support the hypothesis that it was due to left ventricular mechanoreceptor activation in the setting of an underfilled hypercontractile ventricle.2 However, the recent observation that phase 2 cannot be completely abolished by vagotomy calls this hypothesis into question.4 Furthermore, one recent study reported a high incidence of vasovagal responses during an aggressive tilt table protocol in post–cardiac transplant recipients, the majority of whom presumably would have had cardiac vagal deafferentation.3 As Dickinson5 recently pointed out, however, this would not rule out a role for activation of other cardiopulmonary receptors in the atria and great veins. Other possible mechanisms of the failure of reflex constriction might include an abnormality of arterial baroreceptor function, the central command reflex, or the skeletal metaboreceptor reflex. We do not believe that an impairment of peripheral responsiveness to α-adrenergic stimulation is the explanation. First, this would not explain the paradoxical vasodilation during exercise, and second, the pressor response to phenylephrine was normal in patients with vasovagal syncope. The normal response to handgrip implies that central command and skeletal metaboreceptor reflexes are intact.31 We have previously reported normal integrated baroreceptor sensitivity and normal carotid baroreflex sensitivity in patients with vasovagal syncope.32 This implies normal arterial baroreflex function and normal central integration at least of these reflexes. Thus, our data support an abnormality of the afferent limb of the cardiac baroreflex.
While this study makes the important observation that forearm vascular responses during dynamic leg exercise are abnormal in patients with vasovagal syncope, the cause remains speculative.
The forearm vascular responses during dynamic leg exercise may not necessarily reflect those in the quantitatively more important splanchnic vascular bed. In our previous studies in patients with hypertrophic cardiomyopathy, however, forearm vascular responses during leg exercise paralleled changes in invasively measured systemic vascular resistance.21 22 Other studies in normal subjects compared with patients after cardiac transplantation suggested that changes in renal and forearm vascular resistance paralleled each other.19
In patients with vasovagal syncope, there is paradoxical forearm vasodilation or attenuated forearm vasoconstriction during dynamic leg exercise. The attendant exaggerated fall in systemic vascular resistance may be responsible for the exercise syncope that we and others have reported in patients with otherwise normal hearts. The observation that forearm vascular responses during exercise are not infrequently abnormal in patients without a history of exercise syncope/presyncope presumably reflects their ability to markedly augment cardiac output. The mechanism of these abnormal exercise forearm vascular responses remains to be clarified. Possibilities include a primary abnormality of cardiopulmonary receptors, activation of cardiopulmonary receptors as a result of central volume depletion because of a failure of exercise-induced venoconstriction, or some undefined abnormality of cardiovascular control mechanisms in patients with vasovagal syncope. Our data support an abnormality of the afferent limb of the cardiac baroreflex.
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 1994.
- Received February 27, 1995.
- Revision received May 3, 1995.
- Accepted May 6, 1995.
- Copyright © 1995 by American Heart Association
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