B-type natriuretic peptides (BNPs) have been investigated as biomarkers for risk stratification of patients with syncope. Their concentration can be influenced by age and co-morbidities. In the present study, we compared the change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels within 6 hours in patients with vasovagal and arrhythmic syncope to determine whether this change can predict arrhythmic syncope. Using a case-control design, 33 patients were enrolled. Of the 33 patients, 18 with arrhythmic syncope, as they underwent controlled ventricular tachycardia or ventricular fibrillation (VF) during device safety testing of an implantable cardioverter defibrillator implantation or battery replacement, were compared with 15 patients, who during a tilt-table test were diagnosed with vasovagal syncope (VS). For each patient, a blood sample for NT-proBNP evaluation was collected at baseline and 6 hours after the episode of ventricular tachycardia, VF, or VS. We calculated the percentage of increase in the 6-hour NT-proBNP concentration between the 2 groups using nonparametric techniques. We also calculated the area under a receiver operating characteristic curve with the 95% confidence intervals. The 6-hour change in the NT-proBNP concentrations between patients who had had an episode of ventricular tachycardia or VF and patients with VS was significantly different, with a median increase of 32% in the ventricular tachycardia or VF group versus 5% in the VS group (p <0.01). The area under a receiver operating characteristic curve to predict arrhythmic syncope was 0.8 (95% confidence interval 0.65 to 0.95). In conclusion, the results of the present study suggest that a 6-hour NT-proBNP increase might be able to predict arrhythmic syncope. Future work is needed to confirm these findings in undifferentiated emergency department patients who present with syncope.
B-type natriuretic peptides (BNPs) have recently been investigated as biomarkers for risk stratification of patients with syncope. To date, only a single absolute plasma concentration of BNP and N-terminal pro–B-type natriuretic peptide (NT-proBNP) has been considered. However, the timing of this single sampling in relation to the event and the patient’s age or co-morbidities have proved to be problematic. Although a single absolute value appears limited, measuring a change in the levels over time could have some value. In a recent work, we reported a significant increase in the plasma concentration of both BNP and NT-proBNP 6 hours after a controlled episode of ventricular tachycardia or ventricular fibrillation (VF). However, in that study, we did not measure the BNPs after a vasovagal event, the most common known cause of syncope. The goal of the present study was to compare the changes in the plasma concentrations of NT-proBNP during a 6-hour period in 2 different experimental models of syncope, vasovagal and arrhythmic syncope.
Methods
A total of 33 patients were considered, 18 were collected from a previously described experimental model of the arrhythmic syncope as they underwent controlled ventricular tachycardia or VF during device safety testing of an implantable cardioverter defibrillator (ICD). These patients were compared with 15 patients who had had a syncopal or near-syncopal episode during a table-tilt test with pharmacologic challenge. All patients provided written informed consent, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
Our assumption was that VF induced in the cardiac electrophysiology laboratory to test ICD functioning would be a unique clinical model mimicking the hemodynamic changes occurring during arrhythmic syncope. The ICD is composed of a subcutaneously placed generator with ≥1 electrodes seated in the cardiac chambers. It is able to sense heart electric activity and, when required, to deliver electric pacing (antibradycardia therapy) or an electric shock (antitachycardia therapy). Therefore, the ICD is generally used to prevent sudden cardiac death. Some investigators have suggested performing tests of pacing, sensing, and cardioversion threshold after implantation to evaluate the functionality of the ICD. Hence, with the patient under sedation, an episode of VF is induced, and the ICD must recognize the arrhythmia and deliver an effective electric shock. This procedure can be performed during both initial implantation and subsequent battery replacement.
The tilt-table test is used to diagnose neurally mediated syncope. It is performed using an electrically driven tilt table, which enables maintenance of the patient in a head-up position without lower limb movements. The experimental protocol we adopted had 3 components. At the beginning, the patient was maintained in a clinostatic position for 5 minutes. Then, the table was tilted to 75°. After 15 minutes, if significant hypotension or syncope had not occurred, 300 to 400 μg of sublingual nitroglycerin were administered, and the test was continued until the development of syncope or near-syncope or for 10 minutes. During the test, continuous electrocardiographic and noninvasive beat-to-beat arterial pressure monitoring were performed. The test was performed in the morning after a period ≥48 hours from the episode of syncope. The patient had fasted for ≥8 hours. The examination findings were considered negative if the patient had not developed syncope or near-syncope. The tilt-table test findings were considered positive whenever the signs and symptoms (e.g., diaphoresis, lightheadedness, nausea, tunnel vision, dizziness, weakness, pallor) of syncope or near-syncope occurred in association with significant hypotension (absence of a peripheral pulse or a pressure reduction of ≥20 mm Hg and a systolic pressure of ≤90 mm Hg).
For each patient, a blood sample for NT-proBNP evaluation was collected at baseline (i.e., before ICD implantation or the tilt-table test) and 6 hours after the episode of VF or vasovagal syncope (VS). The concentration of NT-proBNP for the arrhythmic model was assessed using the Electro Chemo Luminescence kit (Roche Diagnostics, Indianapolis, Indiana). The concentration of NT-proBNP for the vasovagal model was assessed using the Immulite 2000 kit (Siemens Healthcare Diagnostics, Tarrytown, New York). The NT-proBNP variation must be compared with its minimum concentration change that can be considered relevant. This has been defined as the reference change value, which is determined using the analytic variability of the laboratory method and the intraindividual variability of the marker. The reference change value for NT-proBNP amounts to 11%. An internal analysis showed that both the Roche Elecsys and the Siemens Immulite kits have the same analytic variability (4.2%).
For every patient, we calculated the relative variation of the 6-hour NT-proBNP concentration compared with baseline. Variations <1% and those with a negative value were considered variations of 0%. Categorical variables are reported as frequencies and percentages. We used nonparametric techniques to compare continuous variables, reported as the median and range, as appropriate. In particular, the Wilcoxon 2-sample test was used to assess the differences in the plasmatic concentration variation of NT-proBNP between the cases (arrhythmic) and controls (vasovagal). Univariate and multivariate logistic regression analyses were performed to assess the ability of the variation in NT-proBNP to discriminate between cases and controls, adjusting for gender and age. A receiver operating characteristic (ROC) analysis was performed to evaluate the ability of the relative variation in NT-proBNP to detect arrhythmic syncope. The sensitivity and specificity and negative and positive likelihood ratios of the NT-proBNP relative variation, with the 95% confidence intervals, were calculated for some thresholds to maximize the negative and positive likelihood ratios and Youden’s index (sensitivity + specificity−1). The area under the ROC curve with the 95% confidence interval was calculated. A p-value <0.05, 2-tailed, was considered statistically significant. Statistical analyses were performed using the Statistical Analysis Systems statistical software, version 9.2 (SAS Institute, Cary, North Carolina).
Results
The 2 groups were similar in terms of age, although significantly more women were in the VS group (60% vs 22%, p = 0.03). Both groups had many co-morbidities ( Table 1 ). In the VF group, the baseline values of NT-proBNP ranged from 96 pg/ml to a maximum of 5.762 pg/ml. At 6 hours after VF, the mean NT-proBNP concentration was 2.641 pg/ml. The median NT-proBNP concentration at baseline was 1.110 pg/ml; at 6 hours, it was 1.619 pg/ml, and the median percentage of variation was 32%. We did not find any correlation between the duration of the episode of ventricular fibrillation and the NT-proBNP increase. In 4 patients with VF, no increase in NT-proBNP occurred (percentage of variation <11%). No characteristics were found that distinguished these patients from other patients with VF.
| Variable | Case Group (Arrhythmic) (n = 18) | Control Group (Vasovagal) (n = 15) |
|---|---|---|
| Age (yrs) | 68 ± 13 | 72 ± 16 |
| Gender | ||
| Male | 14 | 6 |
| Female ∗ | 4 | 9 |
| ICD implantation | 9 | — |
| Battery replacement | 9 | — |
| Implantation indication | ||
| Ventricular arrhythmias | 14 | — |
| Cardiac arrest | 4 | — |
| Heart failure | 6 | — |
| Coronary artery disease | 10 | — |
| Dilated cardiomyopathy | 14 | — |
| Ischemic | 9 | — |
| Idiopathic | 4 | — |
| Toxic (chemotherapy) | 1 | — |
| Mean ejection fraction (%) | 26.5 ± 7.8 | — |
| Mean VF duration (s) | 13.4 ± 7.6 | — |
| Range of VF (s) | 6–30 | — |
| Co-morbidities | ||
| Arterial hypertension | 16 (89) | 12 (80) |
| Diabetes mellitus type 2 | 5 (28) | 7 (47) |
| Atrial fibrillation | 5 (28) | 4 (27) |
| Coronary artery disease ∗ | 16 (89) | 4 (27) |
| Parkinson’s disease | 0 | 3 (20) |
| Cancer | 3 (18) | 2 (13) |
| Heart failure ∗ | 12 (67) | 2 (13) |
| None | 1 (6) | 2 (13) |
| Syncope | — | 5 (33) |
| Presyncope | — | 10 (67) |
In the VS group, the NT-proBNP baseline values ranged from <20 to 12.486 pg/ml. The mean NT-proBNP value at 6 hours was 1.625 pg/ml. The median value at baseline was 358 pg/ml and at 6 hours was 419 pg/ml, and the median percentage of variation was 5.1%. The 6-hour variation in the NT-proBNP concentration between the patients with an episode of VF and those with vasovagal syncope or presyncope was significantly (p <0.01) different ( Figure 1 ). The logistic regression model confirmed the significant ability of NT-proBNP to discriminate between cases and controls, independent of age and gender (univariate p = 0.025, multivariate p = 0.028). The sensitivity and specificity of the different cutpoints of NT-proBNP change to discriminate vasovagal and arrhythmic syncope are listed in Table 2 . The area under the ROC curve for the NT-proBNP variations was 0.8 (95% confidence interval 0.65 to 0.95; Figure 2 ).
