Abstract
The tilt test is used for the diagnosis of reflex syncope (RS) and is characterized by low sensitivity, especially in athletes. The objective of the study was the implementation of a novel diagnostic strategy for the tilt test without pharmacologic provocation in athletes based on haemodynamic criteria.
A passive tilt test for 30 min was performed in 132 athletes (53 with a history of RS, 79 without RS). Measurement of haemodynamic, heart rate variability (HRV) and baroreflex sensitivity parameters was performed.
Tilt testing yielded 34% sensitivity and 94% specificity. Among negative tilt test responders, the ones with RS had increased heart rate (HR) (89 ± 11 vs 81 ± 10 bpm, p < 0.001), stroke index (SI) (40.2 ± 7.1 vs 35.5 ± 9.7 ml/m2, p = 0.013), cardiac index (CI) (3.5 ± 0.6 vs 2.8 ± 0.8 l/(min·m2), p < 0.001) and decreased total peripheral resistance index (TPRI) (2230 ± 362 vs 2965 ± 725 dyne·s m2/cm5, p < 0.001), low frequency component of HRV (76.2% (49.0–88.4) vs 79.7% (10.2–91.1), p = 0.045) during head-up tilt, compared with those without RS. Receiver-operating characteristic (ROC) curve analysis showed that among athletes with a negative tilt test the area under the curve (AUC) values were 0.727 (0.626–0.828) for HR (p < 0.001), 0.707 (0.611–0.804) for SI (p = 0.001), 0.847 (0.774–0.920) for CI (p < 0.001), 0.830 (0.754–0.905) for TPRI (p < 0.001). Further stratification of negative tilt test responders, characterizing their results as positive when TPRI <2800 dyne·s m2/cm5 and CI >3 l/(min·m2), resulted in 85% sensitivity and 76% specificity.
Our results provide supportive evidence that a novel stratification based on haemodynamic criteria can improve the sensitivity of the tilt test for the diagnosis of RS in athletes.
Introduction
The tilt test is used as part of the complete work-up of transient loss of consciousness to confirm the diagnosis of reflex (neurally mediated) syncope (RS).1 Passive tilt testing (without pharmacologic provocation) is generally characterized by low sensitivity and high specificity.2 The tilt test with pharmacologic provocation (with the use of isoproterenol or nitroglycerin) is applied as a means of increasing sensitivity, but this methodology is associated with an unavoidable decline in specificity.1,3 The magnitude of the decline in specificity with pharmacologic provocation is unpredictable for the tested individual. Pharmacologic provocation may be associated with side effects and is contraindicated in specific populations, such as in cases with uncontrolled hypertension, left ventricular outflow tract obstruction and known arrhythmias, limiting its widespread applicability.1 Furthermore, highly specific measures derived from tilt testing to make the diagnosis of RS are lacking.
Taking into account that RS is by far the most frequent cause of syncope in young people, tilt testing is very frequently applied in young individuals. Since the majority of young individuals are physically active and frequently engaged in regular sports activities, clinicians may have to deal with young athletes presenting with syncope, with the need to perform a tilt test. Regular exercise leads to favourable cardiovascular and cardiac autonomic nervous system adaptations that possibly enhance athletes’ ability to cope with prolonged standing, as indicated by the reported improvement of symptoms of orthostatic intolerance after a period of exercise training.4–7 Therefore, these exercise-related adaptive changes are expected to reduce the sensitivity of tilt testing in athletes. The present study tried to develop a novel strategy for passive tilt testing based on haemodynamic parameters as an alternative to the commonly used strategy with pharmacologic provocation. This methodology was applied in athletes due to the reduced sensitivity of tilt testing in this subpopulation, making the interpretation of tilt test results in athletes too challenging.
Methods
Subjects
A total of 132 athletes (94 males, 38 females) were recruited. All athletes were examined in the Laboratory of Sports Medicine of the Aristotle University of Thessaloniki, in Greece, which is an authorised sports cardiology centre, in the context of preparticipation screening. Among these athletes, 53 were evaluated because of a history of RS within the previous 12 months, while 79 without history of RS volunteered to participate in the study. All the cases with a history of RS had previous vasovagal syncope mediated by orthostatic stress. Inclusion criteria for the study were: 14–40 years old, more than five years of exercise training experience and competition at a regional level in different sports. Exclusion criteria were: smoking, recent alcohol consumption, presence of any chronic disease and use of drugs. All athletes gave a written informed consent. The study protocol was approved by the Ethics Committee of Aristotle University. The subjects were asked to refrain from strenuous physical activity for 24 h before their examination. All subjects underwent a tilt test, for the evaluation of haemodynamics, heart rate variability (HRV) and baroreflex sensitivity, in the morning. All tests were conducted and interpreted by the same cardiologist blinded to the identity of the subjects
Tilt test
The Task Force Monitor (TFM) 3040i device (CNSystem, Graz, Austria) was used.8 After a horizontal supine rest period of 5 min, the tilt table was inclined at 60° head-up position for 30 min. A positive response was defined according to the European Society of Cardiology guidelines for the diagnosis and management of syncope.1 The endpoint of the tilt test was the induction of either reflex hypotension/bradycardia or delayed orthostatic hypotension associated with syncope/presyncope. According to the modified Vasovagal Syncope International Study (VASIS) classification,9 the response to a tilt test was characterized as: (a) mixed, when heart rate (HR) fell at the time of syncope, but HR did not fall to less than 40 bpm or fell to less than 40 bpm for less than 10 s with or without asystole of less than 3 s, and blood pressure (BP) had fallen before the fall of HR; (b) cardioinhibitory, when asystole >3 s or HR <40 bpm for more than 10 s occurred; (c) vasodepressor, when HR did not fall more than 10% from its peak at the time of syncope. No adverse events were observed.
Assessment of haemodynamic parameters
Instantaneous RR intervals (RRIs) and HR were obtained from the electrocardiogram. Continuous arterial BP was obtained noninvasively using photoplethysmography on the right middle finger. Mean arterial BP (MBP) was calculated by numerical integration of the recorded instantaneous BP. The recorded value was calibrated against conventional oscillometric measurements of arterial BP on the left arm. Impedance cardiography was used to obtain a continuous recording of the temporal derivative of the transthoracic impedance (dZ/dt). Stroke volume (SV) was calculated from the impedance signal. Cardiac output (CO) was computed as SV × HR, whereas total peripheral resistance was calculated as MBP divided by CO. Relevant haemodynamic variables were indexed against body surface area (BSA). Stroke index (SI) was calculated by dividing SV by BSA and cardiac index (CI) was the product of SI and HR. Total peripheral resistance index (TPRI) was calculated as MBP divided by CI. The mean values of these haemodynamic parameters during standing were used for statistical analysis.
Baroreflex sensitivity assessment
Baroreflex sensitivity, which reflects the response of HR to a given reduction or elevation in BP, was measured by the TFM in the supine position and following head-up tilt and was analysed by applying the sequence method. Baroreflex sensitivity was assessed from the spontaneously occurring BP rises and falls which were accompanied by counter-regulatory RRI changes. A linear regression between systolic BP (SBP) and RRI was applied to each individual sequence and the mean baroreflex slope of the SBP/RRI relationship was calculated and taken as a measure of spontaneous baroreflex sensitivity. Only regression lines with a squared correlation coefficient r2 > 0.85 were accepted for analysis. The baroreflex sensitivity was the average regression of baroreflex slope for all of the linear regressions plotted for accepted baroreflex sequences. A baroreflex effectiveness index (BEI) was estimated, which shows how often concomitant changes (ramps) in SBP and RRI were detected, and was defined as the ratio of the number of SBP ramps followed by the respective reflex RRI ramps to the total number of SBP ramps.
HRV assessment
Power spectral analysis for HRV was automatically provided by the TFM, using an adaptive autoregressive model. The following indices were reported: total power spectral density, low frequency power (0.05–0.17 Hz), which is considered a nonspecific marker of sympathetic activity, and high frequency power (0.17–0.4 Hz), which indicates cardiac vagal activity, using normalized units (low frequency spectral component of the R-R interval (LFnu-RRI) and high frequency spectral component of the R-R interval (HFnu-RRI) respectively).10 Low frequency/high frequency ratio (LF/HF) ratio, which is considered an index of sympathovagal balance, was calculated.10
Statistical analysis
All statistical analyses were performed using the SPSS 16.0 statistical package for Windows (SPSS Inc., 1989–2007). A Kolmogorov-Smirnof test was used to verify the use of tests for normal distributed parameters. Normally distributed data were expressed as means ± standard error (SE). Parameters with skewed distribution were reported as median (range). Independent-samples t test and Pearson’s correlation analysis were performed for normally distributed parameters, whereas Mann-Whitney U test, Wilcoxon signed-rank test and Spearman’s correlation analysis were performed for non-normally distributed parameters. Receiver-operating characteristic (ROC) curve analysis was used to evaluate whether the studied haemodynamic parameters could discriminate between athletes with a history of RS and the ones without RS. The relevant optimal cutoff values of these parameters were selected to conform with Youden’s index [J = max(sensitivity + specificity–1)]. A two-tailed p value < 0.05 was considered significant.
Results
The mean age of the athletes was 24 ± 9 years. Sixty-nine athletes were participating in dynamic sports and 63 in static ones (RS: 28 dynamic, 25 static, no RS: 41 dynamic, 38 static). On average, they had been practising their sports for more than seven years with a training frequency of six times per week and training duration of 2.5 h. Parameters of haemodynamics, HRV and baroreflex sensitivity of the 53 athletes with a history of RS and 79 athletes without history of RS are shown in Table 1.
Parameters of haemodynamics, heart rate (HR) variability and baroreflex sensitivity during tilt test: (a) in all athletes and (b) in athletes with negative tilt test.
| All athletes | Athletes with negative tilt test | |||||
|---|---|---|---|---|---|---|
| History of RS (n = 53) | No history of RS (n = 79) | p | History of RS (n = 35) | No history of RS (n = 74) | p | |
| HR (bpm) | 89 ± 10 | 81 ± 10 | <0.001 | 89 ± 11 | 81 ± 10 | <0.001 |
| SBP (mm Hg) | 123.4 ± 11.8 | 131.3 ± 13.9 | 0.001 | 126.5 ± 9.6 | 131.2 ± 14.1 | 0.045 |
| DBP (mm Hg) | 78.2 ± 9.2 | 83.1 ± 9.4 | 0.004 | 80.1 ± 8.5 | 83.2 ± 9.3 | 0.091 |
| MBP (mm Hg) | 94.6 ± 9.6 | 99.3 ± 10.5 | 0.011 | 97.2 ± 8.1 | 99.4 ± 10.6 | 0.291 |
| SI (ml/m2) | 39.2 ± 6.4 | 36.1 ± 10.1 | 0.032 | 40.2 ± 7.1 | 35.5 ± 9.7 | 0.013 |
| CI (l/(min·m2)) | 3.5 ± 0.6 | 2.9 ± 0.8 | <0.001 | 3.5 ± 0.6 | 2.8 ± 0.8 | <0.001 |
| TPRI (dyne·s m2/cm5) | 2201 ± 365 | 2918 ± 733 | <0.001 | 2230 ± 362 | 2965 ± 725 | <0.001 |
| LFnu-RRI (%) | 74.2 (49–88.4) | 79.7 (10.2–91.1) | 0.008 | 76.2 (49.0 −88.4) | 79.7 (10.2–91.1) | 0.045 |
| HFnu-RRI (%) | 25.8 (11.6–51.0) | 20.3 (8.9–89.8) | 0.008 | 23.8 (11.6–51.0) | 20.4 (8.9 −89.8) | 0.045 |
| LF/HF | 3.9 (1.1–16.5) | 4.6 (0.3–20.1) | 0.061 | 4.0 (1.1–16.5) | 4.5 (0.3–20.1) | 0.132 |
| Baroreflex slope (ms/mm Hg) | 9.69 (4.93–29.89) | 9.93 (2.01–26.00) | 0.772 | 9.56 (4.94–29.89) | 9.86 (2.01–26.00) | 0.574 |
| BEI (%) | 70.55 (37.42–89.71) | 72.19 (48.49–91.35) | 0.234 | 71.55 (37.42–89.71) | 72.34 (49.49–91.35) | 0.417 |
| All athletes | Athletes with negative tilt test | |||||
|---|---|---|---|---|---|---|
| History of RS (n = 53) | No history of RS (n = 79) | p | History of RS (n = 35) | No history of RS (n = 74) | p | |
| HR (bpm) | 89 ± 10 | 81 ± 10 | <0.001 | 89 ± 11 | 81 ± 10 | <0.001 |
| SBP (mm Hg) | 123.4 ± 11.8 | 131.3 ± 13.9 | 0.001 | 126.5 ± 9.6 | 131.2 ± 14.1 | 0.045 |
| DBP (mm Hg) | 78.2 ± 9.2 | 83.1 ± 9.4 | 0.004 | 80.1 ± 8.5 | 83.2 ± 9.3 | 0.091 |
| MBP (mm Hg) | 94.6 ± 9.6 | 99.3 ± 10.5 | 0.011 | 97.2 ± 8.1 | 99.4 ± 10.6 | 0.291 |
| SI (ml/m2) | 39.2 ± 6.4 | 36.1 ± 10.1 | 0.032 | 40.2 ± 7.1 | 35.5 ± 9.7 | 0.013 |
| CI (l/(min·m2)) | 3.5 ± 0.6 | 2.9 ± 0.8 | <0.001 | 3.5 ± 0.6 | 2.8 ± 0.8 | <0.001 |
| TPRI (dyne·s m2/cm5) | 2201 ± 365 | 2918 ± 733 | <0.001 | 2230 ± 362 | 2965 ± 725 | <0.001 |
| LFnu-RRI (%) | 74.2 (49–88.4) | 79.7 (10.2–91.1) | 0.008 | 76.2 (49.0 −88.4) | 79.7 (10.2–91.1) | 0.045 |
| HFnu-RRI (%) | 25.8 (11.6–51.0) | 20.3 (8.9–89.8) | 0.008 | 23.8 (11.6–51.0) | 20.4 (8.9 −89.8) | 0.045 |
| LF/HF | 3.9 (1.1–16.5) | 4.6 (0.3–20.1) | 0.061 | 4.0 (1.1–16.5) | 4.5 (0.3–20.1) | 0.132 |
| Baroreflex slope (ms/mm Hg) | 9.69 (4.93–29.89) | 9.93 (2.01–26.00) | 0.772 | 9.56 (4.94–29.89) | 9.86 (2.01–26.00) | 0.574 |
| BEI (%) | 70.55 (37.42–89.71) | 72.19 (48.49–91.35) | 0.234 | 71.55 (37.42–89.71) | 72.34 (49.49–91.35) | 0.417 |
BEI: Baroreflex effectiveness index; CI: cardiac index; DBP: diastolic blood pressure; HFnu-RRI: high frequency spectral component of the R-R interval variability in normalized units; LF/HF: low frequency/high frequency ratio; LFnu-RRI: low frequency spectral component of the R-R interval variability in normalized units; MBP: mean blood pressure; RS: reflex syncope; SBP: systolic blood pressure; SI: stroke index; TPRI: total peripheral resistance index.
Data are means ± standard error for normally distributed variables or median (range) for non-normal variables.
Parameters of haemodynamics, heart rate (HR) variability and baroreflex sensitivity during tilt test: (a) in all athletes and (b) in athletes with negative tilt test.
| All athletes | Athletes with negative tilt test | |||||
|---|---|---|---|---|---|---|
| History of RS (n = 53) | No history of RS (n = 79) | p | History of RS (n = 35) | No history of RS (n = 74) | p | |
| HR (bpm) | 89 ± 10 | 81 ± 10 | <0.001 | 89 ± 11 | 81 ± 10 | <0.001 |
| SBP (mm Hg) | 123.4 ± 11.8 | 131.3 ± 13.9 | 0.001 | 126.5 ± 9.6 | 131.2 ± 14.1 | 0.045 |
| DBP (mm Hg) | 78.2 ± 9.2 | 83.1 ± 9.4 | 0.004 | 80.1 ± 8.5 | 83.2 ± 9.3 | 0.091 |
| MBP (mm Hg) | 94.6 ± 9.6 | 99.3 ± 10.5 | 0.011 | 97.2 ± 8.1 | 99.4 ± 10.6 | 0.291 |
| SI (ml/m2) | 39.2 ± 6.4 | 36.1 ± 10.1 | 0.032 | 40.2 ± 7.1 | 35.5 ± 9.7 | 0.013 |
| CI (l/(min·m2)) | 3.5 ± 0.6 | 2.9 ± 0.8 | <0.001 | 3.5 ± 0.6 | 2.8 ± 0.8 | <0.001 |
| TPRI (dyne·s m2/cm5) | 2201 ± 365 | 2918 ± 733 | <0.001 | 2230 ± 362 | 2965 ± 725 | <0.001 |
| LFnu-RRI (%) | 74.2 (49–88.4) | 79.7 (10.2–91.1) | 0.008 | 76.2 (49.0 −88.4) | 79.7 (10.2–91.1) | 0.045 |
| HFnu-RRI (%) | 25.8 (11.6–51.0) | 20.3 (8.9–89.8) | 0.008 | 23.8 (11.6–51.0) | 20.4 (8.9 −89.8) | 0.045 |
| LF/HF | 3.9 (1.1–16.5) | 4.6 (0.3–20.1) | 0.061 | 4.0 (1.1–16.5) | 4.5 (0.3–20.1) | 0.132 |
| Baroreflex slope (ms/mm Hg) | 9.69 (4.93–29.89) | 9.93 (2.01–26.00) | 0.772 | 9.56 (4.94–29.89) | 9.86 (2.01–26.00) | 0.574 |
| BEI (%) | 70.55 (37.42–89.71) | 72.19 (48.49–91.35) | 0.234 | 71.55 (37.42–89.71) | 72.34 (49.49–91.35) | 0.417 |
| All athletes | Athletes with negative tilt test | |||||
|---|---|---|---|---|---|---|
| History of RS (n = 53) | No history of RS (n = 79) | p | History of RS (n = 35) | No history of RS (n = 74) | p | |
| HR (bpm) | 89 ± 10 | 81 ± 10 | <0.001 | 89 ± 11 | 81 ± 10 | <0.001 |
| SBP (mm Hg) | 123.4 ± 11.8 | 131.3 ± 13.9 | 0.001 | 126.5 ± 9.6 | 131.2 ± 14.1 | 0.045 |
| DBP (mm Hg) | 78.2 ± 9.2 | 83.1 ± 9.4 | 0.004 | 80.1 ± 8.5 | 83.2 ± 9.3 | 0.091 |
| MBP (mm Hg) | 94.6 ± 9.6 | 99.3 ± 10.5 | 0.011 | 97.2 ± 8.1 | 99.4 ± 10.6 | 0.291 |
| SI (ml/m2) | 39.2 ± 6.4 | 36.1 ± 10.1 | 0.032 | 40.2 ± 7.1 | 35.5 ± 9.7 | 0.013 |
| CI (l/(min·m2)) | 3.5 ± 0.6 | 2.9 ± 0.8 | <0.001 | 3.5 ± 0.6 | 2.8 ± 0.8 | <0.001 |
| TPRI (dyne·s m2/cm5) | 2201 ± 365 | 2918 ± 733 | <0.001 | 2230 ± 362 | 2965 ± 725 | <0.001 |
| LFnu-RRI (%) | 74.2 (49–88.4) | 79.7 (10.2–91.1) | 0.008 | 76.2 (49.0 −88.4) | 79.7 (10.2–91.1) | 0.045 |
| HFnu-RRI (%) | 25.8 (11.6–51.0) | 20.3 (8.9–89.8) | 0.008 | 23.8 (11.6–51.0) | 20.4 (8.9 −89.8) | 0.045 |
| LF/HF | 3.9 (1.1–16.5) | 4.6 (0.3–20.1) | 0.061 | 4.0 (1.1–16.5) | 4.5 (0.3–20.1) | 0.132 |
| Baroreflex slope (ms/mm Hg) | 9.69 (4.93–29.89) | 9.93 (2.01–26.00) | 0.772 | 9.56 (4.94–29.89) | 9.86 (2.01–26.00) | 0.574 |
| BEI (%) | 70.55 (37.42–89.71) | 72.19 (48.49–91.35) | 0.234 | 71.55 (37.42–89.71) | 72.34 (49.49–91.35) | 0.417 |
BEI: Baroreflex effectiveness index; CI: cardiac index; DBP: diastolic blood pressure; HFnu-RRI: high frequency spectral component of the R-R interval variability in normalized units; LF/HF: low frequency/high frequency ratio; LFnu-RRI: low frequency spectral component of the R-R interval variability in normalized units; MBP: mean blood pressure; RS: reflex syncope; SBP: systolic blood pressure; SI: stroke index; TPRI: total peripheral resistance index.
Data are means ± standard error for normally distributed variables or median (range) for non-normal variables.
Athletes with a history of RS
Among the athletes with RS, 18 subjects had positive tilt tests resulting in a sensitivity of 34%. Among the 18 positive results, 13 were mixed, four were cardioinhibitory and one was vasodepressor. The duration of stand-up phase in the athletes with positive tilt tests was 1152 ± 397 s. In the athletes with RS, head-up tilt resulted in an increase of LFnu-RRI, LF/HF and reduction of HFnu-RRI, baroreflex slope compared with the supine position, whereas BEI did not change (Table 2). The same results were found in the subgroups of athletes with positive and negative tilt tests. Among athletes with RS, there were no significant differences in the parameters of haemodynamics, HRV and baroreflex sensitivity during head-up tilt between subjects with positive and the ones with negative tilt tests, except for SBP (117.5 ± 13.4 vs 126.5 ± 9.6 mm Hg, p = 0.018), diastolic BP (DBP) (74.4 ± 9.6 vs 80.1 ± 8.5 mm Hg, p = 0.033) and MBP (89.5 ± 10.3 vs 97.2 ± 8.1 mm Hg, p = 0.004).
Parameters of heart rate (HR) variability and baroreflex sensitivity, at baseline and during head-up tilt: (a) in athletes with a history of reflex syncope (RS) and (b) without history of RS.
| History of RS | No history of RS | |||||
|---|---|---|---|---|---|---|
| Baseline | Tilt test | p | Baseline | Tilt test | p | |
| LFnu-RRI (%) | 47.8 (18.3–89.4) | 74.2 (49–88.4) | <0.001 | 60.6 (2.3–86.2) | 79.7 (10.2–91.1) | <0.001 |
| HFnu-RRI (%) | 52.2 (10.6–81.7) | 25.8 (11.6–51.0) | <0.001 | 39.4 (13.8–97.7) | 20.3 (8.9–89.8) | <0.001 |
| LF/HF | 1.0 (0.2–7.2) | 3.9 (1.1–16.5) | <0.001 | 1.3 (0.1–6.1) | 4.6 (0.3–20.1) | <0.001 |
| Baroreflex slope (ms/mm Hg) | 26.83 (4.09–99.42) | 9.69 (4.93–29.89) | <0.001 | 18.55 (6.42–82.69) | 9.93 (2.01–26.00) | <0.001 |
| BEI (%) | 66.10 (25.00–100.00) | 70.55 (37.42–89.71) | 0.377 | 74.19 (15.00–100.00) | 72.19 (48.49–91.35) | 0.472 |
| History of RS | No history of RS | |||||
|---|---|---|---|---|---|---|
| Baseline | Tilt test | p | Baseline | Tilt test | p | |
| LFnu-RRI (%) | 47.8 (18.3–89.4) | 74.2 (49–88.4) | <0.001 | 60.6 (2.3–86.2) | 79.7 (10.2–91.1) | <0.001 |
| HFnu-RRI (%) | 52.2 (10.6–81.7) | 25.8 (11.6–51.0) | <0.001 | 39.4 (13.8–97.7) | 20.3 (8.9–89.8) | <0.001 |
| LF/HF | 1.0 (0.2–7.2) | 3.9 (1.1–16.5) | <0.001 | 1.3 (0.1–6.1) | 4.6 (0.3–20.1) | <0.001 |
| Baroreflex slope (ms/mm Hg) | 26.83 (4.09–99.42) | 9.69 (4.93–29.89) | <0.001 | 18.55 (6.42–82.69) | 9.93 (2.01–26.00) | <0.001 |
| BEI (%) | 66.10 (25.00–100.00) | 70.55 (37.42–89.71) | 0.377 | 74.19 (15.00–100.00) | 72.19 (48.49–91.35) | 0.472 |
BEI: Baroreflex effectiveness index; HFnu-RRI: high frequency spectral component of the R-R interval variability in normalized units; LF/HF: low frequency/high frequency ratio; LFnu-RRI: low frequency spectral component of the R-R interval variability in normalized units.
Data are median (range) for non-normal variables.
Parameters of heart rate (HR) variability and baroreflex sensitivity, at baseline and during head-up tilt: (a) in athletes with a history of reflex syncope (RS) and (b) without history of RS.
| History of RS | No history of RS | |||||
|---|---|---|---|---|---|---|
| Baseline | Tilt test | p | Baseline | Tilt test | p | |
| LFnu-RRI (%) | 47.8 (18.3–89.4) | 74.2 (49–88.4) | <0.001 | 60.6 (2.3–86.2) | 79.7 (10.2–91.1) | <0.001 |
| HFnu-RRI (%) | 52.2 (10.6–81.7) | 25.8 (11.6–51.0) | <0.001 | 39.4 (13.8–97.7) | 20.3 (8.9–89.8) | <0.001 |
| LF/HF | 1.0 (0.2–7.2) | 3.9 (1.1–16.5) | <0.001 | 1.3 (0.1–6.1) | 4.6 (0.3–20.1) | <0.001 |
| Baroreflex slope (ms/mm Hg) | 26.83 (4.09–99.42) | 9.69 (4.93–29.89) | <0.001 | 18.55 (6.42–82.69) | 9.93 (2.01–26.00) | <0.001 |
| BEI (%) | 66.10 (25.00–100.00) | 70.55 (37.42–89.71) | 0.377 | 74.19 (15.00–100.00) | 72.19 (48.49–91.35) | 0.472 |
| History of RS | No history of RS | |||||
|---|---|---|---|---|---|---|
| Baseline | Tilt test | p | Baseline | Tilt test | p | |
| LFnu-RRI (%) | 47.8 (18.3–89.4) | 74.2 (49–88.4) | <0.001 | 60.6 (2.3–86.2) | 79.7 (10.2–91.1) | <0.001 |
| HFnu-RRI (%) | 52.2 (10.6–81.7) | 25.8 (11.6–51.0) | <0.001 | 39.4 (13.8–97.7) | 20.3 (8.9–89.8) | <0.001 |
| LF/HF | 1.0 (0.2–7.2) | 3.9 (1.1–16.5) | <0.001 | 1.3 (0.1–6.1) | 4.6 (0.3–20.1) | <0.001 |
| Baroreflex slope (ms/mm Hg) | 26.83 (4.09–99.42) | 9.69 (4.93–29.89) | <0.001 | 18.55 (6.42–82.69) | 9.93 (2.01–26.00) | <0.001 |
| BEI (%) | 66.10 (25.00–100.00) | 70.55 (37.42–89.71) | 0.377 | 74.19 (15.00–100.00) | 72.19 (48.49–91.35) | 0.472 |
BEI: Baroreflex effectiveness index; HFnu-RRI: high frequency spectral component of the R-R interval variability in normalized units; LF/HF: low frequency/high frequency ratio; LFnu-RRI: low frequency spectral component of the R-R interval variability in normalized units.
Data are median (range) for non-normal variables.
Athletes without history of RS
Among the athletes without RS, five subjects had positive tilt tests, resulting in a specificity of 94%. Only one mixed and four cardioinhibitory responses occurred. The duration of stand-up phase in the athletes with positive tilt tests was 1025 ± 404 s. In the athletes without RS, transition from supine position to head-up tilt resulted in an increase of LFnu-RRI, LF/HF and reduction of HFnu-RRI, baroreflex slope, whereas BEI did not change (Table 2). The same results were noted in the subgroups of athletes with positive and negative tilt tests.
Comparison between athletes with and without RS
Table 1 shows that athletes with RS had increased HR, SI, CI, HFnu-RRI and decreased SBP, DBP, MBP, TPRI, LFnu-RRI during head-up tilt compared with athletes without RS. LF/HF tended to be decreased in athletes with RS compared with those without RS. Baroreflex slope and BEI during head-up tilt did not differ between these two groups of athletes.
Athletes with negative tilt tests
Regarding the subgroup of athletes with negative tilt tests, athletes with RS had increased HR, SI, CI, HFnu-RRI and decreased SBP, TPRI, LFnu-RRI compared with those without RS, whereas LF/HF tended to be increased, DBP tended to be decreased and MBP, baroreflex slope and BEI did not differ (Table 1). In the athletes with negative tilt tests, TPRI during standing correlated positively with LFnu-RRI (r = 0.276, p = 0.004) and negatively with HR (r = −0.276, p = 0.004), SI (r = −0.714, p < 0.001) and CI (r = −0.811, p < 0.001).
Table 3 shows the area under the curve (AUC) values of HR, SI, CI, TPRI, after applying ROC curve analysis in athletes with negative tilt tests, for discrimination between athletes with and without RS. Although all these parameters had acceptable discriminatory power, CI and TPRI showed the best AUC values. Firstly, we selected the TPRI ≥ 2800 dyne·s m2/cm5 as a highly specific criterion for the identification of true negative results (Figure 1), because 95% of athletes with negative tilt tests and TPRI ≥ 2800 dyne·s m2/cm5 had no history of RS. Among the remaining athletes with negative tilt tests and TPRI <2800 dyne·s m2/cm5, we selected the optimal cutoff value of CI = 3 l/(min·m2) to conform with Youden’s index. Therefore, by characterizing the results of negative tilt test responders as positive when TPRI <2800 dyne·s m2/cm5 and CI >3 l/(min·m2), the resultant sensitivity was 85% and specificity was 76% (Figure 1). Figure 2 shows the proposed diagnostic algorithm for athletes presenting with syncope.
Area under the curve (AUC) for discrimination between athletes with history of reflex syncope (RS) and those without history of syncope, among negative tilt test responders.
| AUC (95% confidence interval) | SE | p | |
|---|---|---|---|
| HR (bpm) | 0.727 (0.626–0.828) | 0.052 | <0.001 |
| SI (ml/m2) | 0.707 (0.611–0.804) | 0.049 | 0.001 |
| CI (l/(min·m2)) | 0.847 (0.774–0.920) | 0.037 | <0.001 |
| TPRI (dyne·s m2/cm5) | 0.830 (0.754–0.905) | 0.038 | <0.001 |
| AUC (95% confidence interval) | SE | p | |
|---|---|---|---|
| HR (bpm) | 0.727 (0.626–0.828) | 0.052 | <0.001 |
| SI (ml/m2) | 0.707 (0.611–0.804) | 0.049 | 0.001 |
| CI (l/(min·m2)) | 0.847 (0.774–0.920) | 0.037 | <0.001 |
| TPRI (dyne·s m2/cm5) | 0.830 (0.754–0.905) | 0.038 | <0.001 |
CI: cardiac index; HR: heart rate; SE: standard error; SI: stroke index; TPRI: total peripheral resistance index.
Area under the curve (AUC) for discrimination between athletes with history of reflex syncope (RS) and those without history of syncope, among negative tilt test responders.
| AUC (95% confidence interval) | SE | p | |
|---|---|---|---|
| HR (bpm) | 0.727 (0.626–0.828) | 0.052 | <0.001 |
| SI (ml/m2) | 0.707 (0.611–0.804) | 0.049 | 0.001 |
| CI (l/(min·m2)) | 0.847 (0.774–0.920) | 0.037 | <0.001 |
| TPRI (dyne·s m2/cm5) | 0.830 (0.754–0.905) | 0.038 | <0.001 |
| AUC (95% confidence interval) | SE | p | |
|---|---|---|---|
| HR (bpm) | 0.727 (0.626–0.828) | 0.052 | <0.001 |
| SI (ml/m2) | 0.707 (0.611–0.804) | 0.049 | 0.001 |
| CI (l/(min·m2)) | 0.847 (0.774–0.920) | 0.037 | <0.001 |
| TPRI (dyne·s m2/cm5) | 0.830 (0.754–0.905) | 0.038 | <0.001 |
CI: cardiac index; HR: heart rate; SE: standard error; SI: stroke index; TPRI: total peripheral resistance index.
Athletes with negative tilt test. Relationship between cardiac index (CI) and total peripheral resistance index (TPRI) during head-up tilt.
Diagnostic algorithm for reflex syncope in athletes. CI: cardiac index; TPRI: total peripheral resistance index.
Discussion
The results of the present study indicate that the passive tilt test in athletes appears to have low sensitivity (34%) and high specificity (94%) for the diagnosis of RS. Further stratification of negative tilt test responders according to TPRI and CI can substantially improve the sensitivity, without compromising specificity.
The diagnostic yield of the tilt test in athletes
Although, passive tilt testing has generally low sensitivity, the reported sensitivity of tilt testing in athletes in the current study was too low.2 A possible explanation for these results is that exercise training can enhance tolerance to prolonged standing. Consistently, an improvement of symptoms of orthostatic intolerance has been found after a few months period of exercise training.5,6 No previous study has investigated the diagnostic yield of tilt testing in a large number of athletes. Regarding the mechanisms underlying the improved tolerance to orthostatism in athletes, a more favourable tilt-induced response of autonomic nervous activity, with increased sympathetic drive, may exist. Indeed, the passive tilt test was found to produce a greater enhancement of sympathetic drive, reflected by greater enhancement of the LF component of HRV, in trained athletes than in control subjects.11 Further well designed studies are needed to confirm this mechanism. Since there is no ‘gold standard’ for establishing the diagnosis of RS, the estimation of tilt test sensitivity is generally performed with regard to a population with high pretest probability of RS, deemed to be diseased. Thus, the reported sensitivities in literature are estimates and not true values.2
Tilt-induced changes of HRV and baroreflex sensitivity
In the current study, the tilt-induced changes of HRV and baroreflex sensitivity from the supine position were consistent in all subgroups of athletes, regardless of the presence or absence of history of RS and the tilt test result. The transition from supine position to head-up tilt appears to increase the sympathetic activity and decrease parasympathetic activity, accompanied by enhanced baroreflex sensitivity, without affecting BEI. These data are in line with the results of previous studies in nonathletes, except for BEI, for which the relevant data are not clear.12,13 Although, the pattern of tilt-induced changes in autonomic nervous activity found in the present study is consistent with a previous study evaluating a small number of athletes,14 the tilt-induced changes of baroreflex responses in athletes have not been previously investigated.
Differences among athletes with negative tilt tests according to the presence of history of RS
The present study demonstrated that there were substantial differences in tilt-induced responses of haemodynamics and HRV between athletes with RS and those without RS, even in the subgroup of athletes with negative tilt tests. The results of this study indicate that possible interindividual differences in baroreflex sensitivity may not play a significant role in determining the propensity for syncope of some athletes during prolonged standing. Specifically, among athletes with negative tilt tests, the ones with RS appear to have decreased TPRI, reflecting a less effective mechanism of peripheral arterial vasoconstriction, possibly due to decreased activation of sympathetic nervous system, as indicated by the reduced LFnu-RRI and the positive relationship between TPRI and LFnu-RRI. Additionally, these athletes had higher HR and SI, while TPRI was negatively associated with HR and SI, implying the possible existence of a compensatory mechanism for the decreased TPRI, to prevent a major reduction of BP. Possible mechanisms underlying the upregulation of HR and SI in athletes with RS may be the activation of Bainbridge reflex and Frank-Starling mechanism respectively, due to increased venous return compared with athletes without RS.15 Further studies are needed to elucidate the exact mechanisms. The excessive increases of HR and SI, and thus of CI, may indicate the great orthostatism-induced haemodynamic stress that characterizes subjects with RS. Consistently, it has been reported a greater increase in mean HR in patients with a positive tilt tests than in patients with a negative tilt test.16,17 In this aspect, the increased CI appears to compensate for the reduced TPRI in athletes with RS and negative tilt tests, resulting in the maintenance of MBP. These results contradict the common medical belief that subjects with negative tilt tests represent a homogenous whole with normal tilt-induced haemodynamic responses. Although these individuals do not meet the specific endpoints of the tilt test, they appear to exhibit different tilt-induced responses of haemodynamics and autonomic nervous activity, which are not easily recognizable. The most abnormal of these responses possibly underlie the propensity of some individuals for RS, as indicated by a relevant history of RS. Consistently, a previous study found that late haemodynamic changes during a negative passive tilt test predicted the symptomatic response to a subsequent nitroglycerin sensitized tilt test.18 Most of the above-mentioned considerations possibly have a wider applicability not only limited to athletes. Moreover, the existing studies investigating the sensitivity of the tilt test have focused mainly in the comparison between true positive and false negative responders, considering a priori the haemodynamic response of the latter group during tilt testing as normal,2,18 while the comparison between true negative and false negative responders has not been adequately performed yet. The relatively low sensitivity of tilt testing in athletes makes them an ideal target group for the evaluation of the possible mechanisms underlying the false negative tilt test results, as the present study did.
The current study found that the two regulators of MBP, namely TPRI and CI, can differentiate fairly well between true negative and false negative results. It should be underscored that TPRI ≥2800 dyne·s m2/cm5 was highly specific for the identification of true negative results. Using the cutoffs TPRI <2800 dyne·s m2/cm5 and CI >3 l/(min·m2) to characterize the subjects as positive responders, we were able to enhance the diagnostic yield of tilt testing in athletes, by increasing considerably the sensitivity to 85%, with an acceptable decline in specificity to 76%.
The fall of MBP determined the positive test response
In the current study, among athletes with RS, the only significant differences found between the ones with positive and those with negative tilt tests were decreased SBP, DBP and MBP for the former. In other words, both of these two groups exhibited a similar pattern of tilt-induced responses in haemodynamics, HRV and baroreflex sensitivity, though the former one failed to maintain a MBP adequate for normal cerebral perfusion until 30 min. Indeed, it is well known that autoregulation of cerebral circulation ensures a constant cerebral blood flow during changes of MBP, by vasoconstriction when MBP rises and vasodilation when MBP falls.19 Thus, the critical factor for the occurrence of syncope during tilt testing in athletes appears to be the fall of MBP below the lower limit of cerebral autoregulation.
Study strengths and limitations
Strengths of this study include, firstly, the large healthy population-based cohort with acceptable statistical power for stratified analyses and, secondly, the description and assessment of a non-invasive novel strategy aiming at discrimination between athletes with a history of RS and those without RS, which is less time-consuming and less expensive compared with the method with pharmacologic provocation. The results of ROC curve analysis of the present study indicated that the new strategy had an acceptable diagnostic performance. Additionally, this new strategy avoids the limitations of pharmacologic provocation. Specifically, tilt testing with pharmacologic provocation is characterized by an unavoidable and unpredictable decline in specificity and is performed under conditions that are not relevant to the real physiology of standing.1,3 Notably, the only relevant study evaluating the diagnostic performance of tilt tests with pharmacologic provocation in athletes used 80° tilt angle and reported a sensitivity of 79%, which is lower than the 85% sensitivity of the present study with 60° tilt angle.20 Pharmacologic provocation adds to the cost and complexity of the test.3 Furthermore, pharmacologic provocation may be associated with side effects and is contraindicated in specific populations, such as in cases with uncontrolled hypertension, left ventricular outflow tract obstruction and known arrhythmias, limiting its widespread applicability.1
The results of the present study should be interpreted in light of some limitations. Firstly, athletes engaged in different sports were recruited and males predominated over females, while there was no control group of nonathletes. Secondly, the current study did not include a group of athletes undergoing tilt testing with pharmacologic provocation. However, the aim of the present study was not the evaluation of the relative value of the new strategy compared with that performed with pharmacologic provocation, which remains to be investigated. Further prospective studies are needed with athletes presenting with unexplained syncope to validate the proposed cut-off values for TPRI and CI. Furthermore, it should be recognized that the diagnostic evaluation of athletes with syncope represents a particular challenge as the potential causes of their syncope can range from disorders with a benign prognosis, such as the common vasovagal faint, to severe cardiac diseases.21,22 Therefore, the results of any novel diagnostic method evaluating athletes with syncope, should be assessed from a clinical point of view.
Conclusions
In conclusion, the present study showed that passive tilt testing in athletes is characterized by high specificity and low sensitivity. Among the athletes with negative tilt tests, the ones with RS had decreased TPRI and increased CI, accompanied by decreased sympathetic activation, compared with those without RS. Implementation of a novel diagnostic strategy based on TPRI and CI values appears to result in an acceptable diagnostic performance, avoiding the limitations of the pharmacologic provocation. Nonetheless, the relative value of this strategy compared with that performed with pharmacologic provocation remains to be investigated. Further studies are needed implementing the new strategy in nonathletes to support the above-mentioned results.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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