The effect of clinical triggers on tilt-table testing (TTT) responses has not been systematically evaluated. In the present study, we evaluated the effect of clinical triggers on positive responses to TTT potentiated with nitroglycerin (which acts mainly through peripheral dilation) or clomipramine (which acts mainly through a central serotoninergic mechanism). We enrolled 380 consecutive adult patients. In 66 patients, syncope was triggered by emotional distress (central trigger), in 161 by specific situations or prolonged standing (peripheral trigger), and in 153 syncope occurred in the absence of any detectable trigger. Nitroglycerin TTT, performed in 252 patients, consisted of a passive phase of 20 minutes followed, if negative, by sublingual administration of 400 μg nitroglycerin spray and continuation of tilting for 15 minutes. Clomipramine TTT, performed in 128 patients, consisted of 20 minutes of tilting with intravenous administration of 5 mg clomipramine during the first 5 minutes. The positivity of nitroglycerin TTT was greater in patients with clinical triggers (71% central and 75% peripheral) than in those without (36%). With clomipramine TTT, the positivity rate was greater in patients with central triggers (92%) than in those with peripheral triggers (45%) or no triggers (30%). The cardioinhibitory form was more frequent in patients with a central trigger than in the other 2 groups (34% vs 12% and 7%) and with clomipramine TTT than with nitroglycerin TTT (19% vs 11%, respectively). In contrast, mixed or vasodepressor forms were more frequently induced by nitroglycerin TTT (41% vs 24%). In conclusion, the presence of clinical triggers increased the positivity of TTT and influenced the type of response. We found some specificity of nitroglycerin and clomipramine for peripheral and central mechanisms.
Reflex syncope traditionally refers to a heterogeneous group of conditions in which cardiovascular reflexes are activated in response to central triggers (emotional distress) or peripheral triggers (situational or orthostatic). When definite triggers can be identified, the diagnosis is usually considered established, especially if the syncope is associated with typical prodromes owing to autonomic activation (e.g., intense pallor, sweating, and nausea). However, recognizable triggers are often absent. In such cases, the diagnosis remains presumptive and needs to be corroborated by other findings. In these latter patients, a positive response to tilt-table testing (TTT) is usually considered diagnostic of the cause of syncope, in the absence of competing causes. The various forms have the efferent reflex syncope pathway in common, but obviously differ in terms of the afferent pathways. The effect of clinical triggers on positive responses to TTT has not been systematically evaluated. Only a few studies of small selected populations have addressed this topic ; their results are difficult to compare owing to the nonstandardized definition of triggers and predisposing factors and different protocols of execution of TTT. Of the drug challenges used during TTT, nitroglycerin acts mainly through peripheral dilation. In contrast, the recently introduced clomipramine acts mainly through an inhibition of the reuptake of serotonin in the central nervous system.
In the present study, we evaluated the effect of clinical triggers on positive responses to TTT potentiated with nitroglycerin or clomipramine. We hypothesized some specificity of these 2 drugs for peripheral and central mechanisms, respectively. In addition to the purpose of comparing the diagnostic value of the 2 tests in different clinical situations, we also sought to provide new insight into the pathophysiology of reflex syncope.
Methods
In the present single-center, prospective study we enrolled 380 consecutive adult patients—from 2007 to 2009—who had undergone TTT either because they had had one or more episodes of suspected reflex syncope (diagnostic purpose) or because it was of clinical value to demonstrate the susceptibility to reflex syncope to the patient as a part of biofeedback training to initiate physical therapy (i.e., counterpressure maneuvers; therapeutic purpose). The first 252 patients underwent TTT with a nitroglycerin challenge, and the next 128 patients underwent TTT with clomipramine challenge.
According to the European Society of Cardiology guidelines on syncope, reflex syncope was suspected—and TTT was performed for diagnostic purposes—in patients with historical findings compatible with reflex syncope and in the absence of (1) structural heart disease, abnormal electrocardiographic findings, or rhythm disturbances or, if these were present, after a complete workup (including electrophysiologic study when appropriate) with negative findings that made cardiac syncope unlikely; (2) orthostatic hypotension; and (3) nonsyncopal causes of loss of consciousness. According to the same guidelines, vasovagal syncope was diagnosed if syncope was precipitated by emotional distress or orthostatic stress and was associated with typical prodromes due to autonomic activation. Situational syncope was diagnosed if syncope occurred during or immediately after specific triggers.
To provide a blind assignment, the presence and type of triggers were categorized before performing TTT. The patients were assigned to 3 groups according to the historical features of their present and previous syncopal episodes: those in whom a central trigger could be identified, those in whom a peripheral trigger could be identified and those in whom all syncopal episodes had occurred in the absence of any detectable trigger. According to the guidelines, the definitions we used were as follows:
Central trigger: syncope triggered by emotional distress (fear, pain, instrumentation, venipuncture).
Peripheral trigger: syncope triggered by specific circumstances (during or immediately after micturition, defecation, coughing, swallowing, laughing, or eating or immediately after vigorous exercise) or by prolonged standing.
Absence of established trigger: syncope occurred in the absence of any trigger.
In patients with multiple syncopal episodes, syncope could have been induced by either a central or a peripheral trigger; these cases were analyzed. Moreover, in patients with multiple syncopal episodes, syncope could have been induced by different peripheral triggers (i.e., a situation or orthostatic stress); these patients were assigned to the more specific (i.e., situational) trigger.
TTT with a nitroglycerin challenge (nitroglycerin TTT) was performed according to the “Italian protocol,” which consists of a supine pretilt phase of ≥5 minutes, a tilt angle of 60°, a passive phase of 20 minutes. If the test findings were negative, the patient received a fixed sublingual dose of 400 μg nitroglycerin spray administered in the upright position. Tilting was then continued for 15 minutes.
TTT with a clomipramine challenge (clomipramine TTT) was performed according to the protocol proposed by Flevari et al and Theodorakis et al, consisting of a supine pretilt phase of ≥20 minutes, tilt angle of 60°, no passive phase, and 20 minutes of tilting with intravenous administration of 5 mg clomipramine during the first 5 minutes.
We used the same definitions for positive responses for the 2 protocols. Specifically, the end point of TTT was the induction of either reflex hypotension/bradycardia or delayed orthostatic hypotension, associated with syncope or presyncope. Positive reflex responses were classified as cardioinhibitory if reflex hypotension >50 mm Hg associated with a decrease in heart rate to <40 beats/min for >10 seconds or asystole for >3 seconds occurred and as mixed or vasodepressor if reflex hypotension >50 mm Hg occurred in association with mild bradycardia (heart rate at >40 beats/min and asystole did not occur). Delayed orthostatic hypotension was defined as an early slow progressive decrease in blood pressure until symptoms occurred in the absence of bradycardia.
The data are reported as the mean ± SD or as the median with interquartile range, as appropriate. Continuous and categorical variables were compared between groups using Student’s t test and Fisher’s exact test, respectively. A 2-tailed p value <0.05 was considered statistical significant.
Results
The clinical characteristics of the study population are listed in Table 1 . We enrolled 380 consecutive adult patients affected by syncope. In 66 patients, syncope was triggered by emotional distress (central trigger group), in 161, syncope was triggered by specific situations or prolonged standing (peripheral trigger group), and in 153, syncope occurred in the absence of any trigger (no trigger group). The patients with a central trigger were younger (age 52 ± 20 years), had had a longer median history of syncope (10 years, interquartile range 1 to 28), and fewer of them had any cardiac abnormality (12%) than those of the other 2 groups (p <0.05). No difference was observed between the patients with peripheral triggers and those without established triggers. Overall, the nitroglycerin TTT result was positive in 147 of the patients (58%) (including 14 during the passive phase [10% of positive]). The clomipramine TTT result was positive in 62 patients (48%; p = 0.08). The interval to reflex syncope was 23.2 ± 5.4 minutes with nitroglycerin TTT and 9.7 ± 3.1 minutes with clomipramine TTT (p <0.05). The interval to delayed hypotension was 25.5 ± 2.6 minutes for nitroglycerin TTT and 10.2 ± 1.8 minutes for clomipramine TTT (p <0.05).
| Variable | Nitroglycerin (n = 252) | Clomipramine (n = 128) | p Value |
|---|---|---|---|
| Mean age (years) | 62 ± 20 | 62 ± 15 | 0.99 |
| Men | 137 (54%) | 65 (51%) | 0.51 |
| Abnormal electrocardiographic findings and/or structural heart disease | 59 (23%) | 21 (16%) | 0.14 |
| Bundle branch block | 19 (8%) | 8 (6%) | 0.83 |
| Atrial fibrillation | 15 (6%) | 4 (3%) | 0.32 |
| Coronary artery disease | 17 (7%) | 7 (5%) | 0.82 |
| Other (valvular, dilated cardiomyopathy) | 8 (3%) | 2 (2%) | 0.51 |
| History of syncope | |||
| Lifetime number (median, interquartile range) | 2 (1–4) | 2 (1–4) | |
| Duration (years) | 1 (1–8) | 1 (1–8) | |
| Triggers | |||
| Central (emotional distress) | 41 (16%) | 25 (20%) | 0.47 |
| Peripheral | 108 (43%) | 53 (41%) | 0.82 |
| Situational | 52 (21%) | 24 (19%) | 0.69 |
| Prolonged standing | 56 (22%) | 29 (23%) | 1.00 |
| Absent | 103 (41%) | 50 (34%) | 0.74 |
The presence of clinical triggers increased the positivity of TTT with both drug challenges ( Table 2 ). With nitroglycerin TTT, the positivity rate was similar in patients with central triggers and those with peripheral triggers and was twice as great as the rate observed in patients without any trigger. With clomipramine TTT, the greatest positivity rate was observed in patients with central triggers. Interestingly, the patients who had both central and peripheral triggers were those with the greatest positivity rate: 13 (87%) of 15 with nitroglycerin TTT and 10 (100%) of 10 with clomipramine TTT (p = 0.35). The cardioinhibitory form was more frequent in patients with a central trigger than in the other 2 groups, with both the nitroglycerin and clomipramine challenge (overall, 34% vs 12% and 7%; p = 0.001). Mixed or vasodepressor forms were frequent in all groups ( Table 3 ).
| Triggers/Predisposing Factors | Nitroglycerin | Clomipramine | p Value | ||
|---|---|---|---|---|---|
| Patients (n) | Positive (%) | Patients (n) | Positive (%) | ||
| Central (emotional distress) | 41 | 29 (71%) | 25 | 23 (92%) | 0.06 |
| Emotion | 13 | 10 | 10 | 9 | |
| Pain | 22 | 16 | 12 | 11 | |
| Instrumentation, venipuncture | 6 | 3 | 3 | 3 | |
| Peripheral | 108 | 81 (75%) | 53 | 24 (45%) | 0.0004 |
| Situational | 52 | 40 (78%) | 24 | 12 (50%) | 0.03 |
| Post-prandial | 18 | 14 | 10 | 5 | |
| Micturition | 22 | 16 | 5 | 1 | |
| After exercise | 6 | 5 | 2 | 2 | |
| Cough | 3 | 2 | 4 | 2 | |
| Defecation | 3 | 3 | 3 | 2 | |
| Swallowing | 0 | 0 | 0 | 0 | |
| Laughing | 0 | 0 | 0 | 0 | |
| Prolonged standing | 56 | 41 (73%) | 29 | 12 (41%) | 0.005 |
| Absence of triggers | 103 | 37 (36%) | 50 | 15 (30%) | 0.58 |
| p Value | |||||
| Central versus peripheral | 0.68 | 0.0001 | |||
| Peripheral versus absent | 0.0001 | 0.15 | |||
| Central versus absent | 0.0002 | 0.0001 | |||
| Form | Nitroglycerin | Clomipramine | p Value | ||
|---|---|---|---|---|---|
| Total Patients (n) | Positive (%) | Total Patients (n) | Positive (%) | ||
| Overall | 252 | 128 | |||
| Cardioinhibitory | 28 (11%) | 24 (19%) | 0.05 | ||
| Mixed or vasodepressor | 103 (41%) | 31 (24%) | 0.001 | ||
| Delayed orthostatic hypotension | 16 (6%) | 7 (5%) | 0.82 | ||
| Central (emotional distress) | 41 | 25 | |||
| Cardioinhibitory | 10 (24%) | 11 (44%) | 0.11 | ||
| Mixed or vasodepressor | 18 (44%) | 12 (48%) | 0.80 | ||
| Delayed orthostatic hypotension | 1 (2%) | 0 (0%) | 1.00 | ||
| Peripheral | 108 | 53 | |||
| Cardioinhibitory | 11 (10%) | 9 (17%) | 0.31 | ||
| Mixed or vasodepressor | 59 (55%) | 10 (19%) | 0.0001 | ||
| Delayed orthostatic hypotension | 11 (10%) | 5 (9%) | 1.00 | ||
| Absence of triggers | 103 | 50 | |||
| Cardioinhibitory | 7 (7%) | 4 (8%) | 0.75 | ||
| Mixed or vasodepressor | 26 (25%) | 9 (18%) | 0.41 | ||
| Delayed orthostatic hypotension | 4 (4%) | 2 (4%) | 1.00 | ||
| p Value | |||||
| Cardioinhibitory forms | |||||
| Central vs peripheral | 0.03 | 0.02 | |||
| Peripheral vs absent | 0.46 | 0.24 | |||
| Central vs absent | 0.007 | 0.0005 | |||
| Mixed or vasodepressor forms | |||||
| Central vs peripheral | 0.27 | 0.01 | |||
| Peripheral vs absent | 0.0001 | 1.00 | |||
| Central vs absent | 0.04 | 0.01 | |||
| Delayed orthostatic hypotension | |||||
| Central vs peripheral | 0.18 | 0.17 | |||
| Peripheral vs absent | 0.10 | 0.43 | |||
| Central vs absent | 1.00 | 0.55 | |||
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