CLINICAL STUDIES
Distinct hemodynamic profiles in patients with vasovagal syncope: a heterogeneous population
Win-Kuang Shen, MD, FACC*,
Phillip A. Low, MD ,
Robert F. Rea, MD, FACC*,
Christine M. Lohse, BS ,
David O. Hodge, MS and
Stephen C. Hammill, MD, FACC*
* Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
Peripheral Neuropathy Research Laboratory, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
Manuscript received April 22, 1999;
revised manuscript received November 11, 1999,
accepted January 7, 2000.
Reprint requests and correspondence: Dr. Win-Kuang Shen, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905
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Abstract
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OBJECTIVE
The objective was to investigate mechanisms of vasovagal syncope by identifying laboratory techniques that characterize cardiovascular profiles in patients with vasovagal syncope.
BACKGROUND
The triggering mechanisms of vasovagal syncope are complex. The patient population is likely heterogeneous. We hypothesized that distinct hemodynamic profiles are definable with provocative maneuvers.
METHODS
Three groups of subjects were matched for age and gender: 16 patients with a history of syncope and an inducible vasovagal response during passive tilt table testing (70°, 45 min, group I), 16 with a history of syncope, negative passive tilt table testing but positive isoproterenol tilt table testing (0.05 µg/kg per min, 70°, 10 min, group II), and 16 control subjects. Beat-to-beat hemodynamic functions were determined noninvasively by photoplethysmography and impedance cardiography.
RESULTS
At baseline, hemodynamic functions were not different among the three groups (supine). In response to tilt before any symptoms developed, total peripheral resistance decreased 9% ± 14% in group I from baseline supine to tilt position but increased 27% ± 18% in group II and 28% ± 17% in controls (p < 0.001). Responses to isoproterenol were not significantly different between group II and controls in supine position. In response to tilt during isoproterenol infusion before any symptoms developed, total peripheral resistance decreased 24% ± 20% in group II and increased 20% ± 48% in controls (p = 0.002).
CONCLUSIONS
Group I patients may have impaired ability to increase vascular resistance during orthostatic stress. The inability to overcome isoproterenol-induced vasodilatation during tilt is important in triggering a vasovagal response in group II patients. These data suggest that the population with vasovagal response is heterogeneous. Distinct hemodynamic profiles in response to various provocative maneuvers are definable with noninvasive, continuous monitoring techniques.
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Abbreviations and Acronyms
| | BP | = blood pressure | | CO | = cardiac output | | DBP | = diastolic blood pressure | | HR | = heart rate | | MBP | = mean blood pressure | | SBP | = systolic blood pressure | | SV | = stroke volume | | TPR | = total peripheral resistance | | Z | = thoracic impedance |
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The pathophysiology of the vasovagal state is not completely understood. The most likely explanation of how vasovagal syncope is triggered is the Bezold-Jarisch reflex (1–5). The reflex loop includes venous pooling (preload reduction), activation of cardiac mechanoreceptors, transmission via C fibers (i.e., vagal afferents), central integration (nucleus tractus solitarius) and efferent discharge culminating in vasodilation or bradycardia (or both). This, in turn, leads to the hypotension and loss of consciousness associated with vasovagal syncope. Triggering of vasovagal syncope, however, most likely involves mechanisms other than those described by the Bezold-Jarisch reflex. Although cardiac afferents may have a role in this response, they clearly are not obligatory because typical vasodepressor responses may occur after heart transplantation with well-documented sympathetic inhibition in the absence of any significant bradycardia (6–8). Several peripheral (9,10) and central (11–16) neurotransmitters and vasoactive peptides have been suggested to have a role in modulating vasovagal syncope. Although decreases in end-systolic and end-diastolic areas have been observed echocardiographically at the end of tilt table testing in patients with vasovagal syncope (17–19), we recently reported that a significant reduction of end-diastolic volume, estimated by impedance cardiography, was not observed immediately before isoproterenol-induced vasovagal syncope (20).
Divergent observations in plasma concentrations of norepinephrine (21–24) and heart rate (HR) variability (19,25–28) have been reported by various investigators. Consistent observations on humoral and autonomic abnormalities have been difficult to achieve, perhaps because of: 1) the transient and paroxysmal nature of the syndrome, 2) the inability to continuously monitor hemodynamic functions preceding and during a vasovagal response, and 3) multiple triggering mechanisms in a heterogeneous patient population.
A blunted increase in muscle neural sympathetic discharge was reported recently in habitual fainters and a markedly enhanced sympathetic discharge in occasional fainters (29), suggesting that the clinical history and presentation may be correlated with various triggering mechanisms of vasovagal syncope. Pathogenetic triggering mechanisms of vasovagal syncope are likely protean. Combinations and permutations of these mechanisms reflect the complexity and heterogeneity of the patient population. Although precise identification of the triggering mechanisms of vasovagal syncope is key to effective therapy, our ability to differentiate the various mechanisms and subsets of patients is limited.
In this study, we prospectively assessed beat-to-beat, continuous hemodynamic changes in three groups of subjects with distinct responses to tilt table testing: 1) patients with a history of syncope and a vasovagal response during passive tilt table testing; 2) patients with a history of syncope, no vasovagal response to passive tilt table testing, but a positive response during isoproterenol tilt table testing; and 3) control subjects without a vasovagal reaction. We hypothesized that the patient population prone to vasovagal syncope is heterogeneous. Different hemodynamic profiles can be defined with various provocative maneuvers. The overall goal of this study was to investigate the mechanisms that trigger vasovagal syncope by identifying laboratory techniques that can be used to characterize the cardiovascular profiles of patients with vasovagal syncope.
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Methods
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Patient selection.
The study group included 16 patients with inducible vasovagal response during passive tilt table testing (group I) and 16 patients without an inducible vasovagal response to passive tilt table testing but a positive response to isoproterenol tilt table testing (group II). Also included was an age- and gender-matched control group. Patients were selected from a consecutive group of patients who had tilt table testing because of a history of recurrent syncope without any known cardiovascular disease. Control subjects did not have any known cardiovascular disease or history of near syncope, syncope or orthostatic intolerance. The study protocol was approved by the Institutional Review Board of Mayo Foundation. Informed consent was obtained verbally from all patients and in writing from all control subjects.
Tilt table and isoproterenol testing protocol.
Each patient was monitored in the supine position (baseline supine) for 10 min and then at a 70° angle (baseline tilt) for up to 45 min. For patients in group I, the test was terminated when a vasovagal response was induced. For patients in group II, one-stage isoproterenol tilt table testing was performed (30). With the patient supine, a constant isoproterenol infusion was initiated at 0.05 µg/kg per min. When HR reached a steady state with isoproterenol (isosupine), the subject was monitored for another 3 min in the supine position before repeated tilting (isotilt); the test was terminated when a vasovagal response was induced. In the control group, each subject completed the sequential baseline tilt and the isotilt. The duration of the isotilt was 10 min.
Hemodynamic monitoring.
A volume clamp photoplethysmographic blood pressure (BP) probe (Finapres monitor, Ohmeda, Englewood, Colorado) was attached to the left index finger. Thoracic impedance (Z) was measured by four pairs of electrodes attached to the upper and lower thorax and connected to an NCCOM 3-R7 cardiodynamic monitor (Biomed Medical Manufacturing, Ltd, Irvine, California). Fluctuations of Z (correlated with pulsatile aortic flow) were measured by injecting high-frequency and low-intensity alternating current through these electrodes. Stroke volume (SV) was estimated by the following equation:
in which V is the volume of electrical participating tissue, calculated from the patient’s gender, height and adjusted weight; T is ventricular ejection time; Z0 is mean thoracic impedance; and dZ/dt is maximal rate of change of thoracic impedance.
The theoretical basis and validation of estimating SV from thoracic impedance measurements were established by Kubicek et al. (31) and redefined by Bernstein (32,33). Systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure, HR and SV were measured, and beat-to-beat cardiac output (CO) and total peripheral resistance (TPR) were calculated online and displayed continuously during the isoproterenol tilt table test. The reliability and validation of impedance cardiography have been reviewed critically (34–36).
Data acquisition.
The data from hemodynamic monitoring were entered into an IBM personal computer with real- time data acquisition software developed under a program project. The electrocardiogram signal was detected to an accuracy of 2 ms. Instantaneous HR was calculated from the RR interval. The analog output of the finger probe was sampled at 100 Hz. Maximal and minimal points between QRS complexes were converted by the computer (sample rate, 500 Hz) for continuous display and were stored for later analysis.
Data presentation.
During the baseline supine and isosupine stages of the testing protocol, a data point was obtained during each stage while the subject was in a steady-state condition. Each data point was calculated from an average of 15 consecutive artifact-free samples, acquired at a frequency of 1 Hz, so that each point represented a 10- to 20-s epoch. During baseline tilt and isotilt stages, the data point was obtained between 30 s and 60 s after the subject was in the final tilt position. For group II, this data point was obtained before the onset of any symptoms.
Statistical analysis.
Percent changes from baseline for each mechanical or pharmacologic intervention were summarized as mean ± standard deviation. A two-sample t test was used to test differences between groups I and II if the data were normally distributed. If not, the Wilcoxon rank sum test was used. Analysis of variance was used to test differences among groups I and II and the control group if the data were normally distributed. If not, the Kruskal-Wallis test was used. Duncan’s multiple range procedure was used to identify differences among the three groups. All p values were two-sided, and a type I error level of 0.05 was used.
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Results
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Patient and control subject characteristics.
The clinical characteristics of the 16 patients in group I and group II are summarized in Table 1. Of the 16 patients in each group, eight were women and eight were men. The mean age was 38 ± 15 years for group I and 37 ± 13 years for group II (p = 0.6). All patients had a history of recurrent syncope. None had significant cardiovascular disease, and none was taking a vasoactive or diuretic agent at the time of the tilt table test. The mean age for the control group was 39 ± 14 years. The hemodynamic variables were grouped into cardiomotor (HR, SV and CO; Table 2) and vasomotor (SBP, DBP, MBP and TPR; Table 3) functions. Sequential changes during baseline tilt, isosupine and isotilt were compared with baseline supine values.
Baseline supine hemodynamics.
The hemodynamic parameters are summarized in Tables 2 and 3. In the baseline supine position, cardiomotor findings were similar for all three groups (HR, p = 0.3; SV, p = 0.2; CO, p = 0.1), as were vasomotor functions (SBP, p = 0.7; DBP, p = 0.4; MBP, p = 0.5; TPR, p = 0.5).
Response to passive tilt.
In response to tilting in group I (Fig. 1A), HR increased by 25% ± 26%, SV decreased by 5% ± 25% and calculated CO increased by 10% ± 18%, and, in group II, HR increased by 12% ± 15% and SV and CO decreased by 20% ± 12% and 11% ± 7%, respectively. In response to tilting in the control group, HR increased by 12% ± 15% and SV and CO decreased by 19% ± 11% and 14% ± 11%, respectively. The change in stroke volume in group I was significantly different (p = 0.04) from that in the other two groups, as was the change in CO (p < 0.001).
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Figure 1 Percent of change of cardiomotor and vasomotor response to tilt. (A) Percentage change of heart rate, stroke volume and cardiac output from baseline supine to tilt position (70°) in the three groups of subjects: controls, tilt-positive patients and isoproterenol-positive patients. (B) Percentage change in systolic, diastolic and mean blood pressure (BP) and total peripheral resistance from supine to tilt position. *p < 0.05; ***p < 0.001.
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Changes in vasomotor functions in response to passive tilt are shown in Figure 1B. Systolic blood pressure, DBP and MBP increased in the control group and in group II but showed minimal change in group I. Total peripheral resistance decreased 9% ± 14% in group I and increased 27% ± 18% and 28% ± 17% in group II and the control group, respectively. The relative change in TPR in group I was significantly different from that of the other two groups (p < 0.001).
Response to isoproterenol in the supine position.
With subjects supine, cardiomotor function increased in response to isoproterenol in group II and in the control group (Table 2). The percent changes from baseline are displayed in Figure 2A. In group II, this increase was 49% ± 16%, 9% ± 22% and 62% ± 34% for HR, SV and CO, respectively. In the control group, HR, SV and CO increased 67% ± 25%, 10% ± 28% and 78% ± 51%, respectively. These values were not significantly different between the two groups (HR, p = 0.05; SV, p = 0.9; CO, p = 0.5).
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Figure 2 Cardiomotor function and response to isoproterenol between control subjects and isoproterenol-positive patients. (A) Percentage change in heart rate, stroke volume and cardiac output during isoproterenol infusion (0.05 µg/kg per min) in the supine position compared with baseline supine position. (B) Percentage change in heart rate, stroke volume and cardiac output during isoproterenol infusion from supine to tilt position.
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The effects of isoproterenol on the vasomotor functions in the supine position and in comparison with baseline values in group II and in the control group are shown in Table 3. The percent changes from baseline are shown in Figure 3A. Blood pressure was stable in both groups during isoproterenol infusion, but TPR decreased 38% ± 17% in group II and 40% ± 23% in the control group. The differences between the two groups were not significant (p = 0.8, Fig. 3A).
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Figure 3 Vasomotor function in response to isoproterenol. (A) Percentage change in systolic, diastolic and mean blood pressure (BP) and total peripheral resistance during isoproterenol infusion in supine position compared with baseline supine position. (B) Percentage change in systolic, diastolic and mean blood pressure and total peripheral resistance during isoproterenol infusion from supine to tilt position. **p < 0.01; ***p < 0.001.
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Response to tilt during isoproterenol infusion.
Changes in cardiomotor functions immediately after tilting up and before the onset of vasovagal symptoms in group II are summarized in Table 2. The percent changes are shown in Figure 2B. From isosupine to isotilt, HR, SV and CO increased 13% ± 15%, 19% ± 30% and 31% ± 34%, respectively, in group II and 7% ± 17%, 5% ± 30% and 9% ± 36% in the control group. The differences between the two groups were not significant (HR, p = 0.5; SV, p = 0.3; CO, p = 0.1).
The greatest difference between group II and the control group was in vasomotor functions. In the control group, BP increased slightly from the isosupine to the isotilt position (Table 3), and TPR increased 20% ± 48% (Fig. 3B). In comparison, BP decreased slightly in group II from the isosupine to the isotilt position (Table 3). Total peripheral resistance decreased 24% ± 20% immediately after tilting during isoproterenol infusion. The difference between the two groups was significant (p = 0.002).
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Discussion
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Main findings.
Three main observations were made: 1) at baseline, the hemodynamic variables were indistinguishable among group I, group II and the control group; 2) before any symptoms developed (BP remained relatively stable), TPR was significantly lower in group I than in group II and the control group; and 3) although cardiomotor and vasomotor responses were similar in group II and the control group in the supine position during isoproterenol infusion, vasomotor decompensation was apparent immediately after tilting up in group II before any symptoms developed.
These observations suggest that, in group I, the activation of vascular resistance during orthostatic challenge may be impaired. In group II the inability to overcome isoproterenol-induced vasodilatation during tilting is an important factor preceding a vasovagal response. These data support the idea that the population of patients with vasovagal syncope is heterogeneous. Distinct hemodynamic profiles in response to various provocative maneuvers potentially can be defined by noninvasive, continuous monitoring techniques.
Heterogeneous population.
The pathophysiologic, or the exaggerated physiologic, response of vasovagal syncope has been thoroughly investigated in the last 40 years (3–5,9,12,17,19,24,27,28,37–50). The mechanisms underlying the "triggering" component of the vasovagal response are still elusive. Considerable effort has been made to assess baroreceptor regulation in patients prone to vasovagal syncope. Augmented cardiopulmonary receptor sensitivity has been reported; for example, Sneddon and colleagues (47) observed exaggerated forearm vasoconstriction during the application of subhypotensive lower body negative pressure in patients with vasovagal syncope. In this study, forearm vascular resistance was compared in 17 patients with and 17 patients without a positive response to tilt table testing. A normal control group was not included. In contrast, changes in forearm venous volume were indistinguishable between patients with vasovagal syncope and normal controls during similar testing procedures by Thomson and colleagues (50), whereas a paradoxical forearm vasodilatation and a reduced splenic venous volume response were observed in the patient group during exercise. In this study, TPR was estimated from impedance cardiography, reflecting a systemic and a "net" rather than a regional response. Patient heterogeneity and multiplicity of mechanisms are potential contributors to these different observations. It is important to recognize that the assessment of cardiopulmonary baroreceptor function was made indirectly by inducing preload reduction and measuring forearm resistance. Difficulties remain in clearly distinguishing between a primary cardiopulmonary baroreceptor dysregulation and abnormalities in the afferent or efferent organs or a central mechanism.
Power spectral analysis of RR variability has allowed the balance between parasympathetic and sympathetic activities to be assessed (19,25–28,51,52). An increase (19,28), a decrease (25,26) and no change (27) have been observed in HR in patients with vasovagal syncope. Furlan et al. (28) recently reported different patterns of autonomic changes preceding a vasovagal event. One group of patients had evidence of progressive sympathetic activation and another group had sympathetic inhibition, as estimated by HR variability. By microneurographic techniques, Mosqueda-Garcia and colleagues (29) also reported a blunted muscular neural sympathetic discharge preceding a vasovagal response in habitual fainters and marked enhancement in the neurosympathetic discharge in occasional fainters. Although these observations clearly support the idea that different groups of patients have different autonomic patterns immediately before a vasovagal response, a cause-and-effect relationship cannot be established.
Our data support the impression that normal subjects and patients with vasovagal syncope have subtle differences in vasomotor function. Furthermore, differences also exist among those with vasovagal syncope. These subtle differences can be detected by orthostatic and pharmacologic challenges in conjunction with beat-to-beat changes in cardiovascular variables. This observation is important because these differences may represent the most "proximal" organ abnormality, within the neurocardiogenic reflex, that would be the true "trigger" of this reflex arc.
In our study design, the time segment between 30 and 60 s after a subject was tilted up was selected for analysis a priori. During the intermediate phase after tilting, any short-term adjustments are mediated primarily by the cardiovascular reflexes. Humoral contributions to maintain and reinforce reflexes usually do not occur until prolonged orthostatic stress persists (53). During this time segment, all subjects were asymptomatic. Hemodynamic responses likely reflect baseline cardiovascular regulation and precede the tilt-induced vasovagal response subsequently occurring in the patient population.
Abnormal vasomotor response and clinical implications.
In patients with a history of vasovagal syncope and an inducible vasovagal response during passive tilt (group I), TPR is significantly lower, whereas SV and CO are higher than in control subjects and those with a vasovagal response induced by isoproterenol (group II) (Figs. 1 and 2). We believe these data reflect a subtle impairment of the primary vasoconstrictive mechanism rather than a reflexogenic mechanism because these changes were obtained immediately after tilting and before any vasovagal symptoms developed (54). It remains difficult to differentiate a primary increase in cardiomotor function from a primary decrease in vasomotor function. In the absence of any evidence of vasoconstriction, our data are more consistent with the hypothesis that vasomotor impairment is the primary mechanism. It is also essential to point out that these subtle abnormalities could not have been detected without the ability to analyze beat-to-beat information. Clinically, no differences could be detected with HR or BP.
The differences between the control group and group II are distinguishable only during isoproterenol infusion. The hemodynamic responses to baseline tilt were indistinguishable between the two groups. A failure to overcome the isoproterenol (beta2 receptor activation) mediated vasodilatation appears to be the key component of the initiating mechanism. These observations are consistent with those of our previous report (55).
The ability to differentiate triggering mechanisms of vasovagal response is important. Mosqueda-Garcia and colleagues (29) recently reported that differences in muscle neural sympathetic discharges could be correlated with a patient’s history of frequent versus occasional fainting. Microneurography directly monitors neural transmission but is invasive and is still an investigational tool. Furlan and colleagues (28) reported distinctive patterns of HR variability preceding the vasovagal response in first-time fainters. Heart rate variability analysis, although noninvasive, requires off-line analysis and careful interpretation. Our study reports for the first time that patient populations can be differentiated by clinically approved testing modalities on the basis of potential triggering mechanisms. If a mechanism-based therapy can be proved useful, the potential clinical applications of a mechanism-based testing protocol will be enormous.
Study limitations.
The precision of hemodynamic values, the basis of our study, is limited by the impedance cardiography technique (34–36). Although our data suggest that the peripheral vasculature could be the initiating component of the vasovagal cascade, abnormalities in the other portions of the afferent, central and efferent neurocardiovascular reflex arc cannot be excluded. Also, the estimated TPR does not allow us to differentiate the venous from arterial contribution. Additional studies are needed to further investigate the basic mechanisms of vasomotor dysfunction in patients with vasovagal syncope.
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Footnotes
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Drs. Shen and Low were supported by Program Project Grant PPG NS3 2952 from the National Institutes of Health, which also supported the development of software for data acquisition.
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