Abstract
Aims
Syncope is a common condition with many possible causes, ranging from benign to life-threatening aetiologies. Establishing a diagnosis can be difficult, and specialized syncope units, using cardiovascular autonomic tests (CATs), including a head-up tilt test, can increase the diagnostic yield. However, up to one-fifth of examined patients have inconclusive CAT results. The aim of the present study was to investigate the predictive value of history, and clinical findings for unexplained syncope after CAT and characterize the group with negative results.
Methods and results
Consecutive syncope patients [n = 2663, 61% women, median age 52 (32–69) years] were evaluated and CAT explained aetiology of syncope in 79% of cases, whereas 21% remained unexplained. Predictors of negative CAT were older age at first syncope (+8% higher odds per 10-year increment, P = 0.042), higher supine heart rate (HR; +12% per 10 b.p.m.; P = 0.003), absence of prodromes (+48%; P < 0.001), hypertension (+45%; P = 0.003), diabetes (+82%; P < 0.001), heart failure (+98%; P = 0.014), and coronary artery disease (+51%; P = 0.027). Compared with vasovagal syncope, patients with negative CAT were older, reported more often the absence of prodromes, and had a higher burden of cardiovascular comorbidities.
Conclusion
A cardiovascular autonomic test established the cause of syncope in 79% of patients evaluated in a syncope unit. Syncope without prodromes and cardiovascular comorbidities were significant predictors of failure to reveal an aetiology from assessment by CAT. These are known risk factors for cardiac syncope and patients with inconclusive CAT warrant further investigation.
Keywords: Syncope, Cardiovascular autonomic tests, Head-up tilt test, Unexplained syncope
Graphical Abstract
Graphical Abstract.
What’s new?
New, simple definition of complex syncope: it consists of there being two or more detectable conditions that could cause syncope in a single patient. This has been found to be a useful clinical group.
Using cardiovascular autonomic test (CAT; tilt, active stand, carotid sinus massage, and Valsalva), a diagnosis is possible in close to 80% of patients with syncope unexplained by the initial assessment.
Syncope without prodromes and cardiovascular comorbidities predicts failure to make a diagnosis by CAT.
When a diagnosis cannot be made by CAT, patients require further testing as cardiac structural abnormalities are likely.
Introduction
Syncope is a common condition with many possible causes, ranging from relatively benign aetiologies such as vasovagal reflex to potentially life-threatening cardiac syncope.1
The initial syncope evaluation includes a thorough history, physical examination, and electrocardiogram.1 Triggering factors and symptoms associated with syncope presentation can suggest a diagnosis, such as syncope precipitated by pain, fear, or standing, accompanied by the typical symptoms of nausea, pallor, and sweating in vasovagal syncope (VVS).1
Previous studies have investigated the value of clinical history as a predictor of syncope diagnosis.2–5 Establishing a diagnosis can be difficult, especially in older patients who more often have atypical presentation such as absent/brief prodromes or falls.6–8 In a meta-analysis of 43 315 syncope patients presenting to the emergency department, 42% were admitted to the hospital and 29% were discharged without a diagnosis.9 Unexplained syncope after hospitalization was associated with increased cardiovascular morbidity and mortality.10 In a tertiary centre, it was shown that the use of European Society of Cardiology (ESC) guidelines had a high diagnostic yield, accuracy, and safety. History was the most important aspect. The results showed a low rate of misdiagnosis of <10% but for all serious conditions diagnosed.11 Channelopathies, which typically present in younger patients, are essential to recognize as they carry a risk of sudden death.12,13 Among these patients, arrhythmic syncope is relatively rare14,15 with other more benign aetiological forms being more common, nevertheless still presenting diagnostic difficulties.
Specialized syncope units have proved to be useful to evaluate syncope patients and can increase the diagnostic yield.16 Cardiovascular autonomic tests (CATs) that include Valsalva manoeuvre, carotid sinus massage (CSM), active standing, and head-up tilt test (HUT) can reveal hypotensive susceptibility to vasovagal reflex and cardiovascular autonomic dysfunction as syncope aetiology. However, up to 20% of examined patients have normal haemodynamic parameters during CAT and syncope aetiology cannot be established.17 There is limited knowledge about the association between clinical findings and syncope diagnoses after assessment in a syncope unit, with a focus on patients with inconclusive CAT. A deeper understanding of factors associated with negative CAT can lead to improved diagnostic pathways, such as earlier identification of patients who might receive implantable loop recorder (ILR)18 in parallel or prior to CAT.
The aim of the present study was to characterize the group of patients with negative CAT results and investigate the predictive value of history and clinical findings for negative CAT in patients evaluated for unexplained syncope in a tertiary syncope unit.
Methods
Patient population
Patients were recruited from the previously described SYSTEMA cohort,19,20 which includes patients referred from primary care and hospitals in southern Sweden for investigation of syncope and severe orthostatic intolerance to the tertiary syncope unit at Skåne University Hospital in Malmö. Prior to referral, initial evaluation was carried out according to the ESC syncope guidelines,1 and patients with non-syncopal loss of consciousness and confirmed cardiac syncope were excluded.
Patients were severely symptomatic, with recurrent or traumatic syncope, associated with very brief or no prodromes, and constituted a diagnostic dilemma for the referring physician.
Between August 2008 and May 2021, 3029 consecutive patients were included in SYSTEMA, and of these, 2663 patients had unexplained syncope after the initial evaluation1 and were included in the analysis.
This study complies with the Declaration of Helsinki. The regional ethical review board in Lund, Sweden, approved the study protocol (reference number 82/2008) and all study participants gave written informed consent.
Examination protocol
Patients completed a questionnaire on medical history and syncope-related symptoms.
The investigation included Valsalva manoeuvre, CSM, active standing, and standard HUT performed according to the Italian protocol,21 i.e. a drug-free HUT phase of 20 min or until syncope occurred and the addition of 400 μg of sublingual nitroglycerine for another 15 min if the drug-free phase was negative. It should be noted that the Italian protocol has recently been recommended to have the passive phase reduced to 10 min without loss of diagnostic accuracy. However, the present study was completed before these recommendations were published.22 Electrocardiogram and beat-to-beat blood pressure were monitored continuously by a validated non-invasive photoplethysmographic method.23,24
Diagnostic criteria
Vasovagal syncope was defined as a characteristic pattern of hypotension followed by bradycardia with exacerbation of hypotension accompanied by typical symptoms/syncope.
Orthostatic hypotension (OH) was defined as a sustained decrease in systolic blood pressure (SBP) ≥20 mmHg or diastolic blood pressure (DBP) ≥10 mmHg during HUT, including classical (beginning immediately in the upright position) and delayed OH (beginning >3 min after being upright with a slight rise or no change in HR).25 Immediate OH (iOH) was defined as a rapid and transient (within 15–40 s of standing) decrease in SBP ≥40 mmHg or DBP ≥20 mmHg associated with typical symptoms.26
Carotid sinus syndrome (CSS) was classified as a symptomatic response to CSM in a previously syncopal patient (a fall in SBP of ≥50 mmHg and/or ventricular pause of ≥3 s).1,26 All included patients in this group presented syncope in their history, but when challenged with CSM, supine, and erect, not all had a reproduction of syncope. Some had no prodrome for their syncope, so had nothing with which to compare. However, all had symptoms, usually pre-syncope, despite some not sustaining syncope. Consequently, the authors felt confident that these patients would, in many or the majority of centres, be classified as CSS.
Complex syncope was defined as the detection of ≥2 concomitant diagnoses (CSS, VVS, and OH) during CSM and HUT that could contribute to syncopal episodes. This is a new classification group prompted by the relatively frequent overlap between diagnoses that was encountered.17
Orthostatic hypotension and VVS were diagnosed in the same patient during HUT if there first was a sustained decrease in blood pressure as defined above, and then a rapid decrease in blood pressure and HR leading to syncope, as previously proposed.27
Negative CAT was defined as a normal haemodynamic response to CAT including HUT.
Psychogenic pseudosyncope (PPS) was defined as an apparent loss of consciousness during HUT with no decrease or modest increase in blood pressure and normal or accelerated HR, and characteristic features as previously defined.28 Cases that were difficult to interpret were resolved by adjudication involving a senior physician and the examining physician.
Statistical analysis
The main characteristics of the study population are presented as mean and standard deviation for normally distributed continuous variables, as median and interquartile range for non-normally distributed variables and number with percentages for categorical variables. For comparisons, Pearson’s χ2 test was used for categorical variables and analysis of variance test, Kruskal–Wallis test, the Student’s t-test and Mann–Whitney U test were used for continuous variables as appropriate. A logistic regression model was applied by entering clinical history and symptoms associated with syncope as the independent variable and negative CAT as the dependent variable. Statistical analyses were carried out using IBM SPSS Statistics version 28 (SPSS Inc., Chicago, IL, USA). All tests were two-sided and P < 0.05 was considered significant.
Results
Consecutive patients (n = 3029) were referred for investigation of unexplained syncope or orthostatic intolerance and 2663 patients aged ≥15 years [61% women, median age 52 (32–69) years] had unexplained syncope, were examined by CAT, and were included in the analysis.
Figure 1 shows the proportion of CAT diagnoses in 2663 patients. In 79% of patients, a diagnosis was achieved by CAT and in 21% no diagnosis could be made. Vasovagal syncope as a single diagnosis was present in 42% of patients. Complex syncope was present in 16%, OH in 10%, postural orthostatic tachycardia syndrome (POTS) and CSS in 4% each, and PPS in 2% of patients. Immediate OH was present in 1% of patients.
Figure 1.
The proportion of CAT diagnoses in 2663 patients with unexplained syncope. CAT, cardiovascular autonomic test; CSS, carotid sinus syndrome; iOH, immediate orthostatic hypotension; OH, orthostatic hypotension; POTS, postural orthostatic tachycardia syndrome; PPS, psychogenic pseudosyncope; VVS, vasovagal syncope.
Clinical characteristics, supine haemodynamic values, and syncope-associated symptoms stratified according to the CAT diagnosis group are presented in Table 1.
Table 1.
Clinical characteristics and resting haemodynamic values in 2663 patients with unexplained syncope according to the final CAT diagnosis group
| Clinical features | VVS n = 1111 (42%) |
Neg. CAT n = 546 (21%) |
Complex syncope n = 440 (16%) |
OH n = 268 (10%) |
POTS n = 107 (4%) |
CSS n = 96 (4%) |
PPS n = 58 (2%) |
iOH n = 37 (1%) |
P-value Omnibus test |
|---|---|---|---|---|---|---|---|---|---|
| Age, median (IQR) | 40 (26–57) | 54 (35–71) | 67 (52–75) | 72 (61–79) | 28 (22–36) | 74 (66–80) | 31 (23–42) | 54 (38–67) | <0.001 |
| Female gender, n (%) | 724 (65) | 347 (64) | 230 (52) | 130 (49) | 88 (82) | 35 (37) | 50 (86) | 26 (70) | <0.001 |
| Supine SBP (mean ± SD) | 129 ± 19 | 135 ± 21 | 139 ± 22 | 139 ± 24 | 125 ± 15 | 138 ± 18 | 125 ± 19 | 129 ± 18 | <0.001 |
| Supine DBP (mean ± SD) | 74 ± 11 | 76 ± 12 | 75 ± 11 | 75 ± 12 | 76 ± 12 | 73 ± 11 | 75 ± 13 | 74 ± 9 | 0.013 |
| Supine HR (mean ± SD) | 69 ± 11 | 72 ± 12 | 70 ± 12 | 72 ± 11 | 82 ± 15 | 69 ± 12 | 72 ± 13 | 70 ± 14 | <0.001 |
| No. of previous syncope episodes, median (IQR) | 5 (2–10) | 4 (2–10) | 4 (2–10) | 5 (2–10) | 3 (2–10) | 4 (2–10) | 30 (11–100) | 5 (2–10) | <0.001 |
| Prodromes, n (%) | 652 (59) | 238 (44) | 196 (45) | 89 (34) | 69 (65) | 29 (32) | 37 (64) | 19 (51) | <0.001 |
| Palpitations, n (%) | 270 (24) | 119 (22) | 82 (19) | 40 (15) | 34 (32) | 10 (11) | 27 (47) | 8 (22) | <0.001 |
| Dizziness, n (%) | 750 (68) | 393 (72) | 302 (69) | 212 (79) | 96 (90) | 63 (66) | 50 (86) | 35 (95) | <0.001 |
| Syncope with traumatic injuries, n (%) | 574 (52) | 310 (57) | 216 (49) | 184 (69) | 52 (49) | 57 (61) | 40 (69) | 19 (51) | <0.001 |
| Supine syncope, n (%) | 215 (19) | 89 (16) | 62 (14) | 15 (6) | 17 (16) | 7 (7) | 41 (71) | 2 (5) | <0.001 |
| Hypertension, n (%) | 159 (14) | 179 (33) | 179 (41) | 113 (43) | 4 (4) | 48 (50) | 3 (5) | 10 (28) | <0.001 |
| Diabetes, n (%) | 44 (4) | 65 (12) | 42 (10) | 33 (12) | 3 (3) | 15 (16) | 2 (3) | 0 (0) | <0.001 |
| Heart failure, n (%) | 13 (1) | 21 (4) | 7 (2) | 14 (5) | 1 (1) | 5 (5) | 0 (0) | 0 (0) | <0.001 |
| Atrial fibrillation, n (%) | 40 (4) | 56 (10) | 36 (8) | 54 (20) | 0 (0) | 14 (15) | 0 (0) | 2 (6) | <0.001 |
| CAD, n (%) | 31 (3) | 48 (9) | 33 (8) | 34 (13) | 1 (1) | 17 (18) | 1 (2) | 3 (8) | <0.001 |
CAD, coronary artery disease; CAT, cardiovascular autonomic testing; CSS, carotid sinus syndrome; DBP, diastolic blood pressure; HR, heart rate; iOH, immediate orthostatic hypotension; OH, orthostatic hypotension; POTS, postural orthostatic tachycardia syndrome; PPS, psychogenic pseudosyncope; SBP, systolic blood pressure; VVS, vasovagal syncope.
The age distribution (age at examination by decade) stratified according to the CAT diagnosis group is presented in Figure 2. The prevalence of VVS as a single diagnosis was highest around the age of 20 years and decreased with age. The frequency of negative CAT was even across the 20–50-year age group but slightly higher in the 60–70-year age group.
Figure 2.
Age distribution (number of patients by age decade) stratified according to the CAT diagnosis group. CAT, cardiovascular autonomic test.
The prevalence of complex syncope was bimodal with a small peak at age 20–25 years and a large peak at 70–75 years. The prevalence of OH increased with age, with a peak at 70 years. The prevalence of POTS and PPS was highest around age 20 years. The prevalence of CCS increased with age and was highest around 75 years. The prevalence of iOH was even across the 20–60-year age group and decreased in patients 70 years and older.
Predictors of negative cardiovascular autonomic testing
Table 2 shows the predictive value of clinical parameters and syncope symptoms for a negative CAT workup. Older age at examination, older age at first syncope, higher supine SBP and HR, absence of prodromes, hypertension, diabetes, heart failure, atrial fibrillation, and coronary artery disease were univariate predictors of negative CAT.
Table 2.
Predictors of negative CAT
| Odds ratio | 95% CI | P-value | |
|---|---|---|---|
| Age (per 10-year increment) | 1.06 | 1.02–1.11 | 0.008 |
| Age at first syncope (per 10-year increment) | 1.07 | 1.03–1.11 | 0.001 |
| Gender | 1.13 | 0.93–1.38 | 0.208 |
| Supine SBP (per 10 mmHg) |
1.06 | 1.01–1.10 | 0.013 |
| Supine HR (per 10 b.p.m.) |
1.12 | 1.04–1.20 | 0.002 |
| No. of previous syncope episodes | 1.00 | 0.99–1.00 | 0.650 |
| Absence of prodromes | 1.56 | 1.28–1.90 | <0.001 |
| Palpitations | 1.07 | 0.83–1.37 | 0.607 |
| Dizziness | 1.05 | 0.85–1.29 | 0.675 |
| Supine syncope | 0.90 | 0.70–1.16 | 0.424 |
| Trauma | 1.12 | 0.93–1.36 | 0.232 |
| Hypertension | 1.51 | 1.23–1.85 | <0.001 |
| Diabetes | 1.93 | 1.41–2.63 | <0.001 |
| Heart failure | 2.08 | 1.22–3.56 | 0.007 |
| Atrial fibrillation | 1.54 | 1.12–2.13 | 0.009 |
| CAD | 1.61 | 1.13–2.28 | 0.008 |
CAD, coronary artery disease; CAT, cardiovascular autonomic testing; HR, heart rate; SBP, systolic blood pressure.
In a logistic regression model adjusted for age and gender (Table 3), older age at first syncope (+8% higher odds per 10-year increment, P = 0.042), higher supine HR (+12% per 10 b.p.m., P = 0.003), absence of prodromes (+48%, P < 0.001), hypertension (+45%, P = 0.003), diabetes (+82%, P < 0.001), heart failure (+98%, P = 0.014), and coronary artery disease (+51%, P = 0.027) were significant predictors of negative CAT. Supine SBP and atrial fibrillation were not significant predictors of negative CAT.
Table 3.
Predictors of negative CAT in a logistic regression model adjusted for age and gender
| Odds ratio | 95% CI | P-value | |
|---|---|---|---|
| Age at first syncope (per 10-year increment) |
1.08 | 1.00–1.02 | 0.042 |
| Supine SBP (per 10 mmHg increment) |
1.00 | 0.99–1.01 | 0.222 |
| Supine HR (per 10 b.p.m.) |
1.12 | 1.04–1.20 | 0.003 |
| Absence of prodromes | 1.48 | 1.20–1.83 | <0.001 |
| Hypertension | 1.45 | 1.14–1.85 | 0.003 |
| Diabetes | 1.82 | 1.32–2.51 | <0.001 |
| Heart failure | 1.98 | 1.15–3.42 | 0.014 |
| Atrial fibrillation | 1.40 | 0.99–1.98 | 0.053 |
| CAD | 1.51 | 1.05–2.18 | 0.027 |
CAD, coronary artery disease; CAT, cardiovascular autonomic testing; HR, heart rate; SBP, systolic blood pressure.
Compared with VVS patients (Table 4), negative CAT patients were older (median age 54 vs. 40 years, P < 0.001), had higher blood pressure and supine HR, had fewer previous syncope episodes, reported prodromes less frequently (44 vs. 59%, P < 0.001), and had a higher proportion of hypertension, diabetes, heart failure, atrial fibrillation, and coronary artery disease. There was a tendency for a higher proportion of syncope with traumatic injuries in the negative CAT group. However, reported palpitations, orthostatic dizziness, and supine syncope did not differ between groups.
Table 4.
Clinical characteristics and resting haemodynamic values in patients with VVS compared with negative CAT
| Clinical features | VVS n = 1111 |
Negative CAT n = 546 | P-value |
|---|---|---|---|
| Age, median (IQR) | 40 (26–57) | 54 (35–71) | <0.001 |
| Female gender, n (%) | 724 (65) | 347 (64) | 0.518 |
| Supine SBP, mean ± SD | 129 ± 19 | 135 ± 21 | <0.001 |
| Supine DBP (mean ± SD) | 74 ± 11 | 76 ± 12 | 0.001 |
| Supine HR (mean ± SD) | 69 ± 11 | 72 ± 12 | <0.001 |
| No. of previous syncope episodes, median (IQR) | 5 (2–10) | 4 (2–10) | <0.001 |
| Prodromes, n (%) | 652 (59) | 238 (44) | <0.001 |
| Palpitations, n (%) | 270 (24) | 119 (22) | 0.585 |
| Dizziness, n (%) | 750 (68) | 393 (72) | 0.050 |
| Syncope with traumatic injuries, n (%) | 574 (52) | 310 (57) | 0.047 |
| Supine syncope, n (%) | 215 (19) | 89 (16) | 0.070 |
| Hypertension, n (%) | 159 (14) | 179 (33) | <0.001 |
| Diabetes, n (%) | 44 (4) | 65 (12) | <0.001 |
| Heart failure, n (%) | 13 (1) | 21 (4) | <0.001 |
| Atrial fibrillation, n (%) | 40 (4) | 56 (10) | <0.001 |
| CAD, n (%) | 31 (3) | 48 (9) | <0.001 |
CAD, coronary artery disease; CAT, cardiovascular autonomic testing; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; VVS, vasovagal syncope.
Discussion
This study investigated the predictive value of history and clinical findings for inconclusive cardiovascular autonomic testing. In 2663 patients evaluated in a syncope unit, CAT explained aetiology of syncope in 79% of cases, whereas 21% remained unexplained. Older age at first syncope, higher supine HR, absence of prodromes, hypertension, diabetes, heart failure, and coronary artery disease were significant predictors of negative CAT. Compared with VVS, patients with negative CAT were older, reported the absence of prodromes more frequently, and had a higher proportion of cardiovascular comorbidities.
The age distribution of negative CAT differed from the other diagnosis groups (Figure 2). Vasovagal syncope, POTS, and PPS had the highest prevalence in younger patients. The prevalence of OH and CSS increased the greater the age. The prevalence of negative CAT was even across the 20–50-year age group and slightly higher in the 60–70-year age group. Similar results were reported by Romme et al.,29 the frequency of no diagnosis after syncope evaluation in 503 patients was even across age groups. If most cases of negative CAT were cardiac syncope, we would expect the patients to be older; however, the patients referred to the syncope unit were highly selected, and it is possible that arrhythmia as a cause of syncope was missed during initial evaluation. We have previously reported the frequency of second-line testing before referral to the syncope unit.17 About 60% of patients with negative CAT had been evaluated by echocardiography and/or Holter monitor and 30% by exercise test. The diagnostic yield of Holter monitoring in syncope is low and has been reported around 10%;30 therefore, arrhythmia as a cause of syncope is not improbable.
Predictors of negative cardiovascular autonomic testing
The frequency of negative CAT in the present study was 21%, a number that will be dependent on the referral pattern to the syncope unit. A previous study of 1058 patients undergoing HUT in a syncope unit reached a similar frequency of unexplained syncope after complete evaluation.31 Older age at first syncope, higher supine HR, absence of prodromes, a history of hypertension, diabetes, heart failure, and CAD were significant predictors of negative CAT (Table 3). We have previously reported that patients with early onset syncope and either persistence or recurrence more often had VVS as the aetiology of syncope.17 Syncope without prodromes and the presence of cardiovascular disease are known risk factors for cardiac syncope. A previous study reported age over 60 years, male gender, structural heart disease, low number of syncope episodes, supine and effort syncope, and absence of prodromes as significant predictors of cardiac syncope.32 A meta-analysis of 38 843 patients compared with controls showed that unexplained syncope was associated with a 13% increase in all-cause mortality and the association was stronger in older, diabetic, and/or hypertensive patients,33 stressing the importance of continued evaluation of patients with negative CAT.
If history and clinical characteristics of patients with VVS and negative CAT were similar, it would imply that VVS could be the cause of syncope in the latter group. However, we found that compared with VVS, negative CAT patients were older, had higher blood pressure and supine HR, reported fewer previous syncope episodes, had a higher proportion of absence of prodromes, hypertension, diabetes, heart failure, atrial fibrillation, and CAD. The ISSUE 3 trial34 found older patients with VVS (mean age 63 years) presented differently with short or no prodromes and negative HUT. Their ILR findings mainly revealed a diagnosis of VVS. However, 20% showed atrioventricular block, which was also concluded to be reflex in origin from close inspection of the tracings, identical clinical histories, and complete lack of progression of conduction tissue disease over a period of 2 years. Furthermore, the evolution of VVS over time appears to show that cardioinhibition diminishes and vasodepression increases, thus also changing the presentation of VVS.35 Differences between patients with VVS and negative HUT have previously been reported in smaller studies. In a study of 87 patients undergoing HUT, those with negative HUT had a higher proportion of absent prodromes compared with VVS patients.36 A report of 341 patients showed that VVS and unexplained syncope were similar in many aspects; however, patients with unexplained syncope were more often male, had a shorter history of syncope, and more post-syncopal symptoms.2 In another study of 873 patients evaluated in a syncope unit, a comparison of VVS patients with those with negative HUT showed that the latter were older and reported prodromes less frequently. Patients with VVS reported syncope with traumatic injuries more often,4 a finding that was not replicated in our study.
The factors that predicted negative CAT in the current study are to a large extent those that also increase the risk of cardiac syncope. Thus, it may be that patients presenting with several of these factors may benefit from a ‘primary ILR strategy’, i.e. receiving an ILR rather than CAT as the first step in the investigation.37 Regardless, an important aspect of negative CAT, including HUT is that these patients should receive an ILR, as emphasized by current ESC syncope guidelines,1 and further corroborated by our observations.37 However, even if an ILR is used, there is still a subset of unexplained syncope patients where the final syncope aetiology cannot be established, an obvious challenge for future research.
Study limitations
The present study has several important limitations. It is a single-centre study albeit with a very wide catchment area. We do not have follow-up data on the final syncope diagnosis in patients with negative CAT/HUT. We know that some patients received ILR following CAT/HUT evaluation, but we do not have complete data on the findings. The investigated population (patients referred to a tertiary syncope unit) are highly selected and may not represent syncope patients in the general population.
The strengths of this study are the inclusion of a large number of patients, all examined with CAT/HUT in a syncope unit setting, and a range of diagnoses was evaluated (VVS, OH, iOH, CSS, complex syncope, PPS, POTS, and negative CAT).
Conclusions
Cardiovascular autonomic testing established a definitive cause of syncope in 79% of patients. Negative cardiovascular autonomic testing in syncope was significantly predicted by the lack of prodromes and cardiovascular comorbidities, which are known risk factors for cardiac syncope; therefore, patients with inconclusive tests warrant further investigation.
Contributor Information
Parisa Torabi, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Clinical Physiology, Skåne University Hospital, Malmö, Sweden.
Viktor Hamrefors, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Cardiology, Skåne University Hospital, Malmö, Sweden.
Richard Sutton, Department of Clinical Sciences, Lund University, Malmö, Sweden; National Heart and Lung Institute, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK.
Michele Brignole, IRCCS Istituto Auxologico Italiano, Faint and Fall Research Centre, Ospedale San Luca, Milano, Italy.
Artur Fedorowski, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Funding
This study was supported by the Swedish Heart Lung Foundation (grant nos. 20160519 and 20190383), Eva and Carl-Eric Larsson Foundation, Crafoord Foundation, Swedish governmental funding of clinical research, and Region Skåne research support.
Data availability
The data on which this study is based will be made available upon any reasonable request.
References
- 1. Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli Aet al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:1883–948. [DOI] [PubMed] [Google Scholar]
- 2. Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli Met al. Diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol 2001;37:1921–8. [DOI] [PubMed] [Google Scholar]
- 3. Sheldon R, Rose S, Connolly S, Ritchie D, Koshman ML, Frenneaux M. Diagnostic criteria for vasovagal syncope based on a quantitative history. Eur Heart J 2006;27:344–50. [DOI] [PubMed] [Google Scholar]
- 4. Rafanelli M, Morrione A, Landi A, Ruffolo E, Chisciotti VM, Brunetti MAet al. Neuroautonomic evaluation of patients with unexplained syncope: incidence of complex neurally mediated diagnoses in the elderly. Clin Interv Aging 2014;9:333–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. de Jong JSY, van Zanten S, Thijs RD, van Rossum IA, Harms MPM, de Groot JRet al. Syncope diagnosis at referral to a tertiary syncope unit: an in-depth analysis of the FAST II. J Clin Med 2023;12:2562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Duncan GW, Tan MP, Newton JL, Reeve P, Parry SW. Vasovagal syncope in the older person: differences in presentation between older and younger patients. Age Ageing 2010;39:465–70. [DOI] [PubMed] [Google Scholar]
- 7. Tan MP, Parry SW. Vasovagal syncope in the older patient. J Am Coll Cardiol 2008;51:599–606. [DOI] [PubMed] [Google Scholar]
- 8. Parry SW, Kenny RA. Vasovagal syncope masquerading as unexplained falls in an elderly patient. Can J Cardiol 2002;18:757–8. [PubMed] [Google Scholar]
- 9. D’Ascenzo F, Biondi-Zoccai G, Reed MJ, Gabayan GZ, Suzuki M, Costantino Get al. Incidence, etiology and predictors of adverse outcomes in 43,315 patients presenting to the emergency department with syncope: an international meta-analysis. Int J Cardiol 2013;167:57–62. [DOI] [PubMed] [Google Scholar]
- 10. Yasa E, Ricci F, Magnusson M, Sutton R, Gallina S, Caterina Ret al. Cardiovascular risk after hospitalisation for unexplained syncope and orthostatic hypotension. Heart 2018;104:487–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. de Jong JSY, Blok MRS, Thijs RD, Harms MPM, Hemels MEW, de Groot JRet al. Diagnostic yield and accuracy in a tertiary referral syncope unit validating the ESC guideline on syncope: a prospective cohort study. Europace 2021;23:797–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Mascia G, Bona RD, Ameri P, Canepa M, Porto I, Parati Get al. Brugada syndrome and syncope: a practical approach for diagnosis and treatment. Europace 2021;23:996–1002. [DOI] [PubMed] [Google Scholar]
- 13. Lieve KV, Wilde AA. Inherited ion channel diseases: a brief review. Europace 2015;17:ii1–6. [DOI] [PubMed] [Google Scholar]
- 14. Português J, Calvo L, Canario-Almeida F, Ribeiro S, Sanfins V, Lourenco A. Spontaneously aborted sudden cardiac death in Brugada syndrome. Rev Port Cardiol 2018;37:545–6. [DOI] [PubMed] [Google Scholar]
- 15. Chauveau S, Le Vavasseur O, Chevalier P. Delayed diagnosis of Brugada syndrome in a patient with aborted sudden cardiac death and initial negative flecainide challenge. Clin Case Rep 2017;5:2022–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Kenny RA, Brignole M, Dan GA, Deharo JC, van Dijk JG, Doherty Cet al. Syncope unit: rationale and requirement—the European Heart Rhythm Association position statement endorsed by the Heart Rhythm Society. Europace 2015;17:1325–40. [DOI] [PubMed] [Google Scholar]
- 17. Torabi P, Rivasi G, Hamrefors V, Ungar A, Sutton R, Brignole Met al. Early and late-onset syncope: insight into mechanisms. Eur Heart J 2022;43:2116–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Quartieri F, Harish H, Calò L, Ebrahim I, Fusco A, Mester Set al. New insertable cardiac monitors show high diagnostic yield and good safety profile in real-world clinical practice: results from the international prospective observational SMART registry. Europace 2023;25:euad068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Nilsson D, Sutton R, Tas W, Burri P, Melander O, Fedorowski A. Orthostatic changes in hemodynamics and cardiovascular biomarkers in dysautonomic patients. PLoS One 2015;10:e0128962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Fedorowski A, Burri P, Struck J, Juul-Möller S, Melander O. Novel cardiovascular biomarkers in unexplained syncopal attacks: the SYSTEMA cohort. J Intern Med 2013;273:359–67. [DOI] [PubMed] [Google Scholar]
- 21. Bartoletti A, Alboni P, Ammirati F, Brignole M, Del Rosso A, Foglia Manzillo Get al. ‘The Italian Protocol’: a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace 2000;2:339–42. [DOI] [PubMed] [Google Scholar]
- 22. Russo V, Parente E, Groppelli A, Rivasi G, Tomaino M, Gargaro Aet al. Prevalence of asystole during tilt test-induced vasovagal syncope may depend on test methodology. Europace 2023;25:263–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Eeftinck Schattenkerk DW, van Lieshout JJ, van den Meiracker AH, Wesseling KR, Blanc S, Wieling Wet al. Nexfin noninvasive continuous blood pressure validated against Riva-Rocci/Korotkoff. Am J Hypertens 2009;22:378–83. [DOI] [PubMed] [Google Scholar]
- 24. Langewouters GJ, Settels JJ, Roelandt R, Wesseling KH. Why use Finapres or Portapres rather than intra-arterial or intermittent non-invasive techniques of blood pressure measurement? J Med Eng Technol 1998;22:37–43. [DOI] [PubMed] [Google Scholar]
- 25. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni Iet al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72. [DOI] [PubMed] [Google Scholar]
- 26. Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli Aet al. Practical instructions for the 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:e43–80. [DOI] [PubMed] [Google Scholar]
- 27. Fedorowski A, van Wijnen VK, Wieling W. Delayed orthostatic hypotension and vasovagal syncope: a diagnostic dilemma. Clin Auton Res 2017;27:289–91. [DOI] [PubMed] [Google Scholar]
- 28. Tannemaat MR, van Niekerk J, Reijntjes RH, Thijs RD, Sutton R, van Dijk JG. The semiology of tilt-induced psychogenic pseudosyncope. Neurology 2013;81:752–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Romme JJ, van Dijk N, Boer KR, Dekker LR, Stam J, Reitsma JBet al. Influence of age and gender on the occurrence and presentation of reflex syncope. Clin Auton Res 2008;18:127–33. [DOI] [PubMed] [Google Scholar]
- 30. Kuhne M, Schaer B, Moulay N, Sticherling C, Osswald S. Holter monitoring for syncope: diagnostic yield in different patient groups and impact on device implantation. QJM 2007;100:771–7. [DOI] [PubMed] [Google Scholar]
- 31. Baron-Esquivias G, Diaz Martin AJ, Del Castillo AM, Quintanilla M, Baron-Solis C, Morillo CA. Head-up tilt test diagnostic yield in syncope diagnosis. J Electrocardiol 2020;63:46–50. [DOI] [PubMed] [Google Scholar]
- 32. Berecki-Gisolf J, Sheldon A, Wieling W, van Dijk N, Costantino G, Furlan Ret al. Identifying cardiac syncope based on clinical history: a literature-based model tested in four independent datasets. PLoS One 2013;8:e75255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Ricci F, Sutton R, Palermi S, Tana C, Renda G, Gallina Set al. Prognostic significance of non-cardiac syncope in the general population: a systematic review and meta-analysis. J Cardiovasc Electrophysiol 2018;29:1641–7. [DOI] [PubMed] [Google Scholar]
- 34. Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn ADet al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012;125:2566–71. [DOI] [PubMed] [Google Scholar]
- 35. Rivasi G, Torabi P, Secco G, Ungar A, Sutton R, Brignole Met al. Age-related tilt test responses in patients with suspected reflex syncope. Europace 2021;23:1100–5. [DOI] [PubMed] [Google Scholar]
- 36. Graham LA, Kenny RA. Clinical characteristics of unexplained syncope and their relationship to tilt table test outcomes. Clin Auton Res 2002;12:88–93. [DOI] [PubMed] [Google Scholar]
- 37. Yasa E, Intzilakis T, Ricci F, Melander O, Hamrefors V, Sutton Ret al. Outcomes of primary vs. delayed strategy of implanting a cardiac monitor for unexplained syncope. J Clin Med 2022;11:1819. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data on which this study is based will be made available upon any reasonable request.