Aims: The purpose of this study was to investigate the predictive value of Calgary Score (CS) and spectral analysis of heart rate variability (HRV) in patients with orthostatic intolerance by tilt testing (TT). Methods: Study population included 180 consecutive patients with syncope suggesting orthostatic intolerance (vasodepressor syncope or orthostatic hypotension) and 31 healthy control subjects, matched for age and gender. CS was applied before the TT for patients with syncope. All subjects were underwent to TT. Holter monitoring was done to record the HRV (Fourier transform), measuring the low-frequency (LF) and high-frequency (HF) components and the LF/HF ratio before and during TT. Results: There was no statistical difference in the basal blood pressure levels and HRV before the TT between patients and the control group. The mean CS was -0.8 and 80% had score ≥ - 2. Of the 104 patients who had a positive response to the test, 52.8% had a vasodepressor response and 47.1% had orthostatic hypotension. For the analysis with receiver operator characteristic curve for the stable variable vasodepressor response, CS showed an area under the curve of 0.696 (95% Cl 0.61 to 0.78, p=0.000), with positive predictive value of 79.4% and negative predictive value of 87.5%, resulting in a likelihood ratio of 3.8. LF and HF showed area under the curve of 0.59 (p=0.04). Conclusions: CS showed a better discriminatory power than the HRV to identify patients with orthostatic intolerance which had vasodepressor response to tilt test.
Syncope is a sudden loss of consciousness with spontaneous and immediate recovery, without the need of electrical or chemical cardioversion. This framework is secondary to cerebral hypoperfusion, with short duration (average 12 seconds) associated with an inability to maintain postural tone . In the general population, the annual number episodes is 18.1 to 39.7 per 1000 patients [1, 2]. Among the causes of syncope, syncope mediated neural reflex is the most frequent, accounting for one third of the causes and reaching 66% of cases in emergency units [3, 4].
Tilt testing is indicated to diagnose different types of orthostatic intolerance in patients in whom this diagnosis was suspected but not confirmed by initial evaluation. A recent meta-analysis showed that the tilt test presents good overall ability to discriminate between symptomatic and asymptomatic controls, but with low sensitivity . The sensitivity of the tilt test was 25% and the specificity was 99% during the passive phase. Considering protocols using pharmacological agents, the sensitivity was 59% and the specificity was 91%.
Some studies have been developed to predict the causes of neurally mediated syncope and the response to tilt testing. The Calgary Score is one of the diagnostic tools for this framework, including seven clinical issues [6, 7]. The point score correctly classified 90% of patients, diagnosing vasovagal syncope with sensitivity of 89% and specificity of 91% . A few studies used changes in heart rate or heart rate variability by spectral analysis to predict the outcome of tilt-testing in patients with vasovagal syncope and also in those with chronic autonomic dysfunction [8-11]. However, there are no studies in the literature on the analysis of the autonomic nervous system and the Calgary Score. Thus, the purpose of this study was to investigate the predictive value of Calgary Score and spectral analysis of heart rate in patients with orthostatic intolerance by tilt testing.
The study population consisted of 180 consecutive patients in sinus rhythm whit recurrence syncope/pre-syncope in last 12 months (or one with physical injury) suggesting orthostatic intolerance (vasodepressor syncope or orthostatic hypotension) and 31 healthy control subjects with no history of syncope, matched for age and gender. The study was conducted after approval of local ethics committee and the patients or their legal representatives gave their consent for inclusion in the study.
All subjects were underwent initial evaluation, which included detailed history, physical evaluation, 12-lead electrocardiogram, and the tilt testing. Patients with cardiac syncope, carotid sinus syncope, cardioinhibitory or mixed response, primary autonomic failure, and drug (included provocative agent) or volume depletion induced syncope and postural orthostatic tachycardia syndrome were excluded. To avoid bias in interpretation of heart rate variability were also excluded patients with a positive response to the tilt testing using pharmacological agents.
|Question||Points (if yes)|
|Is there a history of at least one of bifascicular block, asystole, supraventricular tachycardia, diabetes?||- 5|
|At times have bystanders noted you to be blue during your faint?||- 4|
|Did your syncope start when you were 35 years of age or older?||- 3|
|Do you remember anything about being unconscious?||- 2|
|Do you have lightheaded spells or faint with prolonged sitting or standing?||+ 1|
|Do you sweat or fell warm before a faint?||+ 2|
|Do you have lightheaded spells or faint with pain or in medical settings?||+ 3|
The Calgary Score was applied to the patient during the interview before the tilt testing for patients with syncope. However, their calculation was not known by the attending physician prior to the tilt testing. The score consists of seven diagnostic questions about the medical history, triggers, circumstances and signs and symptoms of syncope (Table 1) [6, 7]. All questions were answered as “yes” or “no”. If a question was answered as ‘yes’, points were added or subtracted. The points for individual questions were summed to obtain a total score (range: -14 to + 6 points). If the total score was - 2 or more positive, a Calgary Score diagnosis of vasovagal syncope was made.
The tilt testing was performed between 8:00 and 11:00 a.m. in a quiet room at a stable temperature. All subjects were fasted overnight prior to the test. The tilting table was electrically driven and equipped with footplate support. A peripheral intravenous cannula was placed before testing to administer IV fluid. After at least 20 minutes in the supine position, the subjects were tilted to an upright position up to 70°. The endpoint of tilt testing is the induction of either reflex hypotension/bradycardia associated with syncope or pre-syncope or the completion of 40 min tilt. Blood pressure (BP) was monitored by a manual sphygmomanometer every 3 minutes or more frequently if necessary. Heart rate was monitored continuously. A vasodepressor response was defined as a sudden drop in systolic BP (lower than 80 mmHg or over 30 mmHg of the basal value) without a decrease in heart rate occurred simultaneously with symptoms of pre-syncope or syncope. Orthostatic hypotension was defined as a symptomatic drop in systolic BP of at least 20 mmHg or in diastolic BP of at least 10 mmHg within 3 minutes (classical orthostatic hypotension) or slow progressive hypotension beyond the first 3 minutes of the testing (delayed orthostatic hypotension).
Heart rate variability (HRV) is a well-known method of noninvasive evaluation of autonomic nervous system activity and was performed according to the guidelines of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology . The spectral analysis of HRV allows, through records of short duration (five minutes), estimate the autonomic balance. In humans, this analysis reveals three major components: ultra low frequency (0.003 to 0.04 Hz), low frequency (LF) (0.04 to 0.15 Hz) and high frequency (HF) (0.15 to 0.40 Hz). Studies have shown a predominant role in parasympathetic activity in modulating the HF component, while the LF component corresponds mainly to the sympathetic tone. Consequently, the LF/HF ratio is considered a measure of sympathovagal balance [12-14].
For analysis of HRV during the tilt test, all subjects underwent by Digital Holter monitoring by using three channels while maintaining normal respiratory rate. This was performed using the program for analysis of Holter DMI/Burdick, ALTAIRPC v 6.00B Holter System, evaluating the spectral analysis by Fourier transform, allowing measurements of the LF, HF and LF/HF ratio. The evaluation of such components was made after a rigorous manual editing of the records, with the elimination of artifacts and correction of arrhythmias. Spectral indices were computed for two short-term intervals: the last 5 min before tilt test in the supine position and was performed on average at the 10th min during the tilt test or the last 5 min before the positive response if it occurred before tenth min. The results of spectral analysis were expressed in absolute units (ms2) and the logarithmic transformation of the results was made.
Statistical analyses were performed with SPSS for Windows version 14.0 (SPSS Inc. Chicago, Illinois). Data are expressed as the mean value ± SD for continuous variables and as frequencies for categorical variables. To compare continuous variables nonparametric methods (Mann-Whitney and Wilcoxon tests) were used and chi-square statistics were used for categorical variables. For the discrimination of subjects with positive response tilt testing and the types of responses by the Calgary Score was used the receiver operator characteristic (ROC) curve . A p value < 0.05 was considered significant.
|Variables||Patients with syncope (n=180)||Controls (n=31)|
|Systolic BP1, mmHg||125.7||120.3||0.15|
|Diastolic BP1, mmHg||79.2||76.9||0.15|
|Heart rate1, bpm||67.8||65.8||0.38|
The mean age of the patients with syncope enrolled was 46.5 ± 21.0 years (range 10 to 87), 103 women, and the mean age of the healthy control subjects (controls) was 39.3 ± 17.9 years (range 19 to 86), 15 women. There was no statistical difference in the age and gender between patients and the control group. The characteristics at baseline and during tilt testing are summarized in Table 2. None of 31 controls had a syncopal episode during the tilting test.
Among patients with a history of syncope, 67.2% had prodrome, 43.8 % physical injury, and the last episode occurred on average time 67.2 days ago (median of 30.0 days ago). The mean number of episodes of syncope was 19.2 (median of 3) during the average time evolution of 38.2 months (median of 12 months). Ninety seven (53.8%) patients had recurrence of syncope ≥ 3 episodes.The mean score of Calgary was -0.8 and 144 patients (80%) had score ≥ - 2. The average time of positive response to tilt testing was 30.1 ± 12.7 min. Of the 104 patients who had a positive response to the test, 55 patients (52.8%) had a vasodepressor response and 49 (47.1%) had orthostatic hypotension.
To compare the spectral analysis before and during the tilt test in all subjects, the Wilcoxon test was performed, which showed a decrease of HF component (1169.1 versus 459.1ms2, p=0.00), increased LF/HF ratio (2.0 versus 11.7, p=0.00) and no significant change of the LF component (950.1 versus 1000.1 ms2, p=0.18). And among patients with syncope, the statistical analysis showed decrease of HF (928.1 versus 485.7 ms2, p=0.00), increased LF/HF (2.1 versus 12.6, p=0.00) e no change of LF (934.0 versus 963.7 ms2, p=0.23). Logarithmic transformation of the components of HRV was taken and the same p-values were obtained.
|Variables||Negative response (n=76)||Vasodepressor response (n=55)||Orthostatic hypotension (n=49)|
|Time evolution (months)||30.9||53.3||32.9||0.15|
|Number of episodes||3.5||5.7||58.0||0.16|
|Last episode (days)||55.2||98.4||58.5||0.31|
|Pts with prodrome||47||45||29||0.02|
|Pts with physical injury||34||21||24||0.53|
|Pts with recurrence ≥ 3||37||33||27||0.43|
|Pts with Calgary score ≥ -2||63||49||32||0.00|
|HF1 – HF2, ms2||662.6||1137.8||316.5||0.00|
When comparing the groups according to the response to tilt test (negative, vasodepressor and orthostatic hypotension), it was observed that there were a lower proportion of patients with prodrome among those with postural hypotension and a higher proportion of patients with Calgary score ≥ - 2 among those with vasodepressor response. No significant differences were found in relation the genders, the recurrence of syncopal episodes and the occurrence of physical injury. And utilizing the Kruskal Wallis test for comparison between those same groups, age was higher among those with postural hypotension, and no difference in the average time evolution of syncope, in the number of episodes and in the interval in days between the last episode and the tilt testing. In the supine position, LF and HF were lower among the patients with orthostatic hypotension. During the tilt testing, LF was also smaller among those patients and there was a tendency to LF/HF ratio of less value. There was no statistical difference in the magnitude of the increase in the LF component and LF/HF ratio among the groups when comparing the periods in the supine position and the tilt testing. Regarding the magnitude of the decrease in the HF component, there is a significant alteration in patients with response vasodepressor with change of position (Table 3). Logarithmic transformation of the components of HRV was taken and the same p-values were obtained.
When applying the operating characteristic curve for the stable variable positive response to tilt test (vasodepressor and orthostatic hypotension response), the Calgary score showed an area under the curve of 0.687 (95% Confidence Interval – CI - 0.599 to 0.775, p = 0.000). Considering only the vasodepressor response, the area under the curve is 0.696 (95% CI 0.610 to 0.782, p = 0.000) (Figure 1). To the cut-off value of -2.5 for Calgary score, the sensibility and specificity were 89.1% and 76.6%, respectively, with positive predictive value of 79.4% and negative predictive value of 87.5%, resulting in a likelihood ratio of 3.8. Considering the response of orthostatic hypotension, the area under the ROC is 0.266. And when applying ROC for the stable variable vasodepressor response to tilt test, LF and HF components showed area under the curve of 0.59 (95% CI 0.507 to 0.680, p=0.04) (Figure 2).
The main finding of this study is the best discriminatory power of the Calgary score for the vasodepressor response to tilt testing compared to spectral analysis in the supine position, with a high negative predictive value and likelihood ratio of 3.8 times for patients with a history of orthostatic intolerance. There is a study that evaluated the power of spectral analysis of heart rate to predict the positive response to tilt testing. In this study with 79 patients and 26 controls, the LF in the supine position may provide a useful index in the diagnosis of orthostatic intolerance with 80% sensitivity and 82% specificity being considered a helpful and low-cost diagnostic tool . Other studies have evaluated the behavior of the autonomic nervous system during tilt test to differentiate patients with vasovagal syncope or heart rate variations in the first minutes of upright tilting, the baroreflex response or transthoracic impedance signal to predict the positive response to the test [9-11, 16-22]. And there are studies to predict the outcome of tilt testing in order to reduce their time of its completion, to predict the outcome to a subsequent nitroglycerin sensitized tilt testing and the recurrence of syncope [9, 23, 24].
Thus, there are several articles on this topic because of limitations regarding tilt testing that include the length of time a test requires and the predictive accuracy of provocative testing with isoproterenol or nitroglycerin. In addition, studies were based on the hypothesis that alterations in autonomic tone are responsible for vasovagal syncope. However, further analysis of heart rate and blood pressure events preceding syncope may provide a better understanding of the pathophysiology of this complex disease .
Nevertheless, no study has evaluated the predictive value of these variables, spectral analysis and the Calgary score, in patients with orthostatic intolerance. The present study demonstrated that the best predictive value of the vasodepressor response to tilt test was the Calgary score, with an area under the curve of nearly 0.70 against 0.59 for the spectral analysis. This can be explained by the different findings from those studies on the behavior of autonomic nervous system by HRV. Some studies showed increased sympathetic tone or heart rate in patients with vasovagal syncope in the upright position [11, 17-19] and others find decrease of LF range or decrease in the mean values of LF and HF while the LF/HF ratio increased, but these changes were not statistically significant [8, 16]. In addition to the contradictory results, the analysis of parameters of heart rate cannot demonstrate differences in the supine position [26, 27].
On the other hand, initial evaluation, which consists in careful history, physical examination and electrocardiogram, is able to define the cause of syncope in up 50% of patients . And Calgary score correctly classified 90% of patients with vasovagal syncope . A study done to validate of the Calgary score demonstrated similar sensitivity but low specificity . This result was attributed to factors such as the selection of patients with atypical manifestations, difficulty in obtaining clinical information and their correct interpretation, and a high percentage of patients with cardiac syncope . Besides these factors, older age also contributes to low specificity, particularly when patients are elderly and with previous history of mild cardiovascular disease . Thus, these data from the literature can explain our results with high sensitivity and specificity for the Calgary score regarding vasodepressor response, but with an area under curve of 0.266 for response of orthostatic hypotension, since patients with this response were older.
To avoid interpretation bias, the two groups were composed: the control group of healthy individuals with no history of syncope and case group of patients with syncope suggesting orthostatic intolerance, matched for age and gender. Because these and other variables such as blood pressure can alter HRV [29, 30], those groups were composed, and no statistical difference was observed in relation to those variables and the components of spectral analysis. And among patients with syncope, we excluded those with cardioinhibitory or mixed response due low predictive value of heart rate in predicting syncope in these responses [9, 31].
Regarding the characteristics of patients, there is agreement with literature data [1, 32] for the proportion of prodrome, physical injury, recurrence of syncope, beyond older age in patients with orthostatic hypotension.
This study was restricted to spectral analysis of HRV. No analyzes for measurement of norepinephrine or other method for assessing autonomic nervous system were made. Because the present study was performed in a single center, it is possible that the demographic characteristics and medical history of the patient differ from those of other institutions.
The Calgary Score showed a better discriminatory power than the HRV to identify patients with orthostatic intolerance which had vasodepressor response to tilt testing with likelihood ratio of 3.8 times. CS is a useful clinical tool that should be applied to the proficiency of the diagnosis of vasovagal syncope even in patients with negative tilt testing.
- Moya A, Sutton R, Ammirati F, Blanc J, Brignole M, Dahm J, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;30:2631-71 pubmed
- Brignole M, Menozzi C, Bartoletti A, Giada F, Lagi A, Ungar A, et al. A new management of syncope: prospective systematic guideline-based evaluation of patients referred urgently to general hospitals. Eur Heart J. 2006;27:76-82 pubmed
- Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M, et al. Diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol. 2001;37:1921-8 pubmed
- Sheldon R, Rose S, Connolly S, Ritchie D, Koshman M, Frenneaux M. Diagnostic criteria for vasovagal syncope based on a quantitative history. Eur Heart J. 2006;27:344-50 pubmed
- Gulli G, Cooper V, Claydon V, Hainsworth R. Cross-spectral analysis of cardiovascular parameters whilst supine may identify subjects with poor orthostatic tolerance. Clin Sci (Lond). 2003;105:119-26 pubmed
- Virag N, Sutton R, Vetter R, Markowitz T, Erickson M. Prediction of vasovagal syncope from heart rate and blood pressure trend and variability: experience in 1,155 patients. Heart Rhythm. 2007;4:1375-82 pubmed
- Duplyakov D, Golovina G, Sysuenkova E, Garkina S. Can the result of a tilt test be predicted in the first five minutes?. Cardiol J. 2011;18:521-6 pubmed
- Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93:1043-65 pubmed
- Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991;84:482-92 pubmed
- Cook N. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation. 2007;115:928-35 pubmed
- Kochiadakis G, Orfanakis A, Chryssostomakis S, Manios E, Kounali D, Vardas P. Autonomic nervous system activity during tilt testing in syncopal patients, estimated by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol. 1997;20:1332-41 pubmed
- Pruvot E, Vesin J, Schlaepfer J, Fromer M, Kappenberger L. Autonomic imbalance assessed by heart rate variability analysis in vasovagal syncope. Pacing Clin Electrophysiol. 1994;17:2201-6 pubmed
- Mallat Z, Vicaut E, Sangare A, Verschueren J, Fontaine G, Frank R. Prediction of head-up tilt test result by analysis of early heart rate variations. Circulation. 1997;96:581-4 pubmed
- Sumiyoshi M, Nakata Y, Mineda Y, Tokano T, Yasuda M, Nakazato Y, et al. Does an early increase in heart rate during tilting predict the results of passive tilt testing?. Pacing Clin Electrophysiol. 2000;23:2046-51 pubmed
- Samniah N, Sakaguchi S, Ermis C, Lurie K, Benditt D. Transient modification of baroreceptor response during tilt-induced vasovagal syncope. Europace. 2004;6:48-54 pubmed
- Bellard E, Fortrat J, Schang D, Dupuis J, Victor J, Leftheriotis G. Changes in the transthoracic impedance signal predict the outcome of a 70 degrees head-up tilt test. Clin Sci (Lond). 2003;104:119-26 pubmed
- Bellard E, Fortrat J, Schang D, Dupuis J, Victor J, Leftheriotis G. Late hemodynamic changes during a negative passive head-up tilt predict the symptomatic outcome to a nitroglycerin sensitized tilt. Pacing Clin Electrophysiol. 2005;28:89-96 pubmed
- Kadish A. Predicting tilt table results. Heart Rhythm. 2007;4:1383-4 pubmed
- Furlan R, Piazza S, Dell'Orto S, Barbic F, Bianchi A, Mainardi L, et al. Cardiac autonomic patterns preceding occasional vasovagal reactions in healthy humans. Circulation. 1998;98:1756-61 pubmed
- Antelmi I, de Paula R, Shinzato A, Peres C, Mansur A, Grupi C. Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease. Am J Cardiol. 2004;93:381-5 pubmed
- Moya A, Rivas N, Pérez-Rodón J, et al. El síncope: un problema con mayúsculas. Rev Esp Cardiol 2010; 10(Supl.A):53-9.