Recent history of vasovagal syncope in a young, referral-based population is a stronger predictor of recurrent syncope than lifetime syncope burden.

INTRODUCTION: accurate selection of patients for vasovagal syncope studies requires strong risk stratification and knowledge of the natural history of syncope. We aimed to test the hypothesis that recent history of vasovagal syncope compared to distant history better predicts subsequent recurrence of syncope. METHODS AND RESULTS: in all, 208 subjects with a positive tilt test and ≥ 3 lifetime syncope spells were followed for 1 year. Syncope episodes in the preceding year and total historical spells were compared for their ability to predict a syncope recurrence using the criteria of optimal statistical significance, best linear separation of risk populations, and impact on power calculations. The number of vasovagal syncope spells in the preceding year better predicted syncope recurrence when compared to total number of historical spells (likelihood ratio statistic 28.4, P < 0.0001; versus 20.4, P = 0.001), and showed a substantial effect as the number of syncope events increased. For example, syncope recurred in 22% of those with <2 spells in the previous year compared to 69% in those with >6 spells. A history of no syncope compared to any syncope in the preceding year was associated with a 1-year probability of 7% versus 46% for syncope recurrence. A study designed to detect a 50% decrease in syncope recurrence at P = 0.05 with 80% power would require 159 patients with at least 3 lifetime spells, and only 108 patients with at least 3 spells in the previous year. CONCLUSIONS: the number of syncope events in the year preceding clinical evaluation is the best predictor of syncope recurrence.

Syncope and structural heart disease: historical criteria for vasovagal syncope and ventricular tachycardia.

INTRODUCTION: to develop evidence-based criteria that distinguish syncope due to ventricular tachycardia (VT) from vasovagal syncope (VVS) in patients with structural heart disease (SHD). METHODS AND RESULTS: one hundred and thirty-four patients with syncope and SHD completed a 118-item questionnaire and underwent noninvasive and invasive diagnostic assessments in a prospective cohort study. The contributions of symptoms to diagnoses were estimated with logistic regression and a point score was developed and then tested using receiver-operator characteristic analysis. The effectiveness of the decision rule was evaluated with long-term outcome. There were 21 patients with tilt-positive VVS, 78 with clinically declared or inducible VT, and 35 with no identified cause of syncope. Six features were significant predictors. Factors that predicted VT included male sex and age at onset >35 years; factors predicting VVS included prolonged sitting or standing; developing presyncope preceded by stress; recurrent headaches; and experiencing fatigue, which lasts longer than 1 minute after syncope. The point score correctly classified 92% of patients, diagnosing VT with 99% sensitivity and 68% specificity. The negative predictive value is ≥ 96%. Fully 67% of patients with undiagnosed syncope were classified as having VT based upon their symptoms. The decision rule predicted 9-year arrhythmia-free survival (VVS 84%, VT 39%, hazard ratio 4.32) and 9-year overall survival (VVS 66%, VT 37%, hazard ratio 2.87). CONCLUSIONS: the causes of syncope in patients with SHD, and their clinical outcomes, can be estimated accurately based on the clinical history. The history safely screens out the possibility of VT as a cause of syncope.

The development and preliminary validation of a scale measuring the impact of syncope on quality of life.

AIMS: To develop a brief syncope-specific measure of health-related quality of life. METHODS AND RESULTS: One hundred and fourteen patients with syncope completed a 48-item questionnaire derived from a generic measure of quality of life (the EQ-5D), the Syncope Functional Status Questionnaire, a depression scale (the CES-D) and historical symptoms. From these, clinical impact methodology was used to derive 12-item Impact of Syncope on Quality of Life (ISQL). The ISQL correlated with the number of syncopal spells in the previous year (r = 0.35), self-perceived health status (r = -0.55), the three scores from the SFSQ: [impairment (r = 0.77), fear and worry (r = 0.72), syncope dysfunction (r = 0.82), and depression (r = 0.62)], illustrating its convergent validity with these concepts. Known group differences were evident between patients who exhibited reduced quality of life on the EQ-5D and those who did not. There was no significant correlation between ISQL score and age or gender. ISQL score correlated better with the frequency of spells in the previous year than years prior to the previous year. CONCLUSION: The ISQL is a brief valid measure of the impact of syncope on quality of life. It measures impairment, fear, depression, and physical limitations, and correlates with recent syncope frequency.

Effect of metoprolol on quality of life in the Prevention of Syncope Trial.

INTRODUCTION: Vasovagal syncope is common, often recurrent, and reduces quality of life. No therapies have proven useful to improve quality of life in adequately designed randomized clinical trials. Beta-blockers have mixed evidence for effectiveness in preventing syncope. METHODS: The Prevention of Syncope Trial was a randomized, placebo-controlled, double-blind, multinational, clinical trial that tested the hypothesis that metoprolol improves quality of life in adult patients with vasovagal syncope in a 1-year observation period. Randomization was stratified in strata of patients <42 and > or =42 years old. The quality of life questionnaires Short Form-36 (SF-36) and Euroqol EQ-5D were completed at baseline and after 6 and 12 months of treatment by 204, 132, and 121 patients, respectively. RESULTS: There were 208 patients, mean age 42 +/- 18, of whom 134 (64%) were females. All had positive tilt tests. There was no improvement in quality of life during the trial in the entire group or in either treatment arm. Patients in the metoprolol treatment arm did not have improved quality of life compared to the patients in the placebo arm using either the SF-36 or EQ5D after either 6 or 12 months. Finally, there was no improvement in quality of life associated with metoprolol use in patients either <42 or > or =42 years of age. CONCLUSION: Metoprolol does not improve quality of life in patients with recurrent vasovagal syncope and a positive tilt test.

Design and use of a quantitative scale for measuring presyncope.

INTRODUCTION: Vasovagal syncope is common and distressing. One important symptom is presyncope, but there are no clinimetric measures of this. We developed the Calgary Presyncope Form (CPF) and used it to test whether metoprolol reduces presyncope in a randomized trial. METHODS: The CPF captures the frequency, duration, and severity of presyncope. We administered it to participants in the Prevention of Syncope Trial (POST), a randomized clinical trial that tested the hypothesis that metoprolol reduces syncope and presyncope in adult patients with vasovagal syncope. RESULTS: The CPF was completed by 44 patients on metoprolol and 39 patients on placebo, of a total of 208 subjects. Completion of the CPF for each of the threedimensions was 84-87% in the 83 respondents. Results were centrally distributed in duration and severity dimensions, but not in frequency. Patients had a median of 1.2 presyncopal spells per day, with a median moderate severity, lasting a median 10 minutes. The 3 scales were statistically independent of each other. These results were independent of subject age, and results in all 3 dimensions were stable over the observation period. There was no significant difference between patients on metoprolol and placebo in any dimension. CONCLUSION: The 3-dimensional CPF is simple, easy to use, stable over time, measures 3 independent variables, and documents that metoprolol does not reduce presyncope.

Worsening of symptoms before presentation with vasovagal syncope.

INTRODUCTION: Much of the natural history of vasovagal syncope is unknown. We determined whether patients presenting for care have had a recently worsened syncope frequency. METHODS AND RESULTS: We compared 208 subjects in the referral-based Prevention of Syncope Trial (POST) and 122 subjects who fainted > or =1 in a community survey study. Their mean ages and gender proportions were similar. The POST population had a higher median lifetime syncope frequency (1.16 vs 0.12 spells/year, P < 0.0001) and more subjects began fainting at age > or =35 years (26% vs 6%, P < 0.0001). In POST, the median frequency of syncopal spells in the preceding year was higher than in all previous years (3 vs 0.57, P < 0.0001). POST subjects presented sooner after their first spell (median 11.0 vs 16.8 years, P = 0.0002), and after their last spell (median 0.3 vs 7.4 years, P < 0.0001). POST subjects > or =35 years old had a shorter history than similar community-survey subjects (2.8 vs 14.9 y, P < 0.0001) and presented earlier after their first syncopal spell than POST subjects with a younger onset of syncope (median 2.8 vs 14.7 y, P < 0.0001), despite having fewer faints (median 6 vs 10, P = 0.0002). CONCLUSIONS: Many syncope patients present for care after a recent worsening of their frequency of syncope.

Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope.

BACKGROUND: Previous studies that assessed the effects of beta-blockers in preventing vasovagal syncope provided mixed results. Our goal was to determine whether treatment with metoprolol reduces the risk of syncope in patients with vasovagal syncope. METHODS AND RESULTS: The multicenter Prevention of Syncope Trial (POST) was a randomized, placebo-controlled, double-blind, trial designed to assess the effects of metoprolol in vasovagal syncope over a 1-year treatment period. Two prespecified analyses included the relationships of age and initial tilt-test results to any benefit from metoprolol. All patients had >2 syncopal spells and a positive tilt test. Randomization was stratified according to ages <42 and > or =42 years. Patients received either metoprolol or matching placebo at highest-tolerated doses from 25 to 200 mg daily. The main outcome measure was the first recurrence of syncope. A total of 208 patients (mean age 42+/-18 years) with a median of 9 syncopal spells over a median of 11 years were randomized, 108 to receive metoprolol and 100 to the placebo group. There were 75 patients with > or =1 recurrence of syncope. The likelihood of recurrent syncope was not significantly different between groups. Neither the age of the patient nor the need for isoproterenol to produce a positive tilt test predicted subsequent significant benefit from metoprolol. CONCLUSIONS: Metoprolol was not effective in preventing vasovagal syncope in the study population.

Age of first faint in patients with vasovagal syncope.

INTRODUCTION: Understanding whether vasovagal syncope is a lifelong disorder might shed insight into its physiology and affect management strategies. Accordingly, we determined the age of the first syncopal spell in adult patients who sought care for syncope. METHODS AND RESULTS: Patients were 42 +/- 18 years old with 64% women. They had had a median 8 syncope spells (interquartile range [IQR]: 4, 20) with a median frequency of 1.0 syncopal spells per year. The range of syncopal spells was 1-3,375, and the range of duration of history of syncope was 0.003-70 years. The first syncopal spell occurred at ages 0-81 in a skewed distribution, with a marked mode age of 13 years, a median age of 18 years (IQR 12, 37), and a mean age of 26 +/- 20 years. The distributions were statistically indistinguishable across countries (P = 0.50), among Canadian regions (P = 0.69), and between the studies (P = 0.49). The same modal values were seen in males and females, and in patients <40 and > or =40 years old. However, patients > or =40 years had median ages of onset older than patients <40 years (36 +/- 23 vs 17 +/- 8 years). Patients had a recalled history of syncopal spells of median duration of 10 years (IQR: 2, 23), with a range of 0.003-70 years. An age of onset <44 years was 86% accurate for vasovagal syncope. CONCLUSION: The most common age at which vasovagal syncope first presents is 13 years, and patients remain at risk of syncope for many years. Lifelong coping strategies may be desirable.

Diagnostic criteria for vasovagal syncope based on a quantitative history.

AIMS: Our goal was to develop historical criteria for the diagnosis of vasovagal syncope. METHODS AND RESULTS: We administered a 118-item historical questionnaire to 418 patients with syncope and no apparent structural heart disease. The prevalence of each item was compared between patients with positive tilt tests and those with syncope of other, known causes. The contributions of symptoms to diagnoses were estimated with logistic regression, point scores were developed, and the scores were tested using receiver operator characteristic analysis. The accuracy of the decision rule was assessed with bootstrapping. Data sets were complete for all subjects. The causes of syncope were known in 323 patients and included tilt-positive vasovagal syncope (235 patients) and other diagnoses such as complete heart block and supraventricular tachycardias (88 patients). The point score correctly classified 90% of patients, diagnosing vasovagal syncope with 89% sensitivity and 91% specificity. The decision rule suggested that 68% of an additional 95 patients with syncope of unknown cause and a negative tilt test have vasovagal syncope. CONCLUSION: A simple point score of historical features distinguishes vasovagal syncope from syncope of other causes with very high sensitivity and specificity.

Activity-responsive pacing produces long-term heart rate variability.

INTRODUCTION: Long-term heart rate variability (HRV) measures, including the standard deviation of means of successive 5-minute epochs of R-R interval intervals (SDANN) and the power law slope (beta), are important prognostic measures, yet their physiologic basis is unknown. We tested the hypothesis that long-term HRV arises from physical activity in a randomized cross-over study in patients with rate-responsive pacemakers. METHODS AND RESULTS: Ten patients with complete heart block and dual-chamber pacemakers underwent 24-hour periods of ambulatory ECG in each of three pacing modes: atrially tracked, fixed-rate, and rate-responsive pacing. SDANN, ultra low frequency (ULF; frequencies <0.0033 Hz), and beta slope were calculated; and high-frequency power and root mean square of consecutive normal R-R intervals (rMSSD) were calculated as measures of short-term HRV, which have autonomic origins. Long-term HRV measures were similar with atrially tracked and rate-responsive pacing and were much greater than in fixed-rate pacing (SDANN P = 0.0001; ULF P = 0.0001; beta slope P = 0.0002). Short-term HRV measures were similarly low in fixed-rate and rate-responsive pacing (P = NS) and were significantly lower than with atrially tracked pacing (P = 0.0034). CONCLUSION: Rate-responsive pacing reproduces long-term, but not short-term, measures of HRV, suggesting that they may be markers of heart rate responses to patient activity.

Similarity of spontaneous and induced heart rate and blood pressure turbulence.

BACKGROUND: Heart rate turbulence (HRT) is a transient tachycardia-bradycardia that follows premature ventricular complexes (PVCs). The physiology of turbulence is studied in the electrophysiology lab using induced premature ventricular stimuli but the reliability of this model for HRT is unknown. OBJECTIVES: To compare heart rate and blood pressure signatures of induced and spontaneous HRT. METHODS: Each patient received 10 ventricular extrastimuli at 1-min intervals. Electrocardiogram and continuous blood pressure results were digitized for 34 electrophysiology patients. RESULTS: Fifteen patients yielded at least one induced and one spontaneous analyzable PVC. Per subject, 3.6+/-2.2 spontaneous and 6.1+/-3.3 induced HRT sequences were detected. Spontaneous and inducible HRT were indistinguishable according to turbulence onset (median -1.7% versus -2.3%, P=0.09), turbulence slope (median 7.1 ms/beat versus 10.0 ms/beat, P=0.73), turbulence tachycardia (median 29 ms versus 22 ms, P=0.97) and turbulence bradycardia (45 ms versus 72 ms, P=0.60). Accompanying blood pressure signatures were indistinguishable according to initial hypotension (-0.5+/-5.9 mmHg versus 12.1+/-5.5 mmHg, P=0.19), hypertension time (7.7+/-3.6 s versus 7.8+/-1.9 s, P=0.93) and turbulence hypertension (13.5+/-5.7 mmHg versus 16.1+/-9.2 mmHg, P=0.19). Baroreflex sensitivities estimated by the spontaneous sequence method were similar for spontaneous and induced turbulence (median 7.5 ms/mmHg versus 7.2 ms/mmHg, P=0.89) and correlated with each other (r2=0.81). Heart rate and blood pressure turbulence induced in the electrophysiology laboratory were similar to those following spontaneous PVCs and induced turbulence was a valid model for study under controlled conditions.

Outcome of patients with dual-chamber pacemakers implanted for the prevention of neurally mediated syncope.

Dual-chamber pacemaker insertion (PI) has been found to reduce the recurrence of neurally mediated syncope (NMS) in 3 randomized trials. However, the long-term benefits of PI are unknown. To assess the natural history of NMS, we followed a cohort of 40 patients who underwent PI for frequent NMS for 46 to 75 months. We assessed the reduction in syncope frequency after PI and the time to first recurrence of syncope. Sixty months after PI, 32.5% of patients remained free of NMS. The frequency of syncope decreased from 0.46 to 0.06 spells/month (before to after PI, p = 0.04). Two groups of patients were identified, with responders to PI defined as having a 75% decrease in the frequency of NMS. Responders (n = 22) experienced a significant decrease in the frequency of NMS (0.31 to 0.01 spells/month, p <0.0001), whereas nonresponders did not experience a similar reduction (p = 0.8). Responders could not be identified by either baseline or tilt-test parameters. Patients without an early recurrence of syncope after PI (within 6 months) experienced a significant reduction in the frequency of NMS (0.24 to 0.02 spells/month, p = 0.0002), although the reduction was not significant (p = 0.3) in patients with an early recurrence of syncope. Some, but not all, patients respond to permanent PI for NMS. The long-term benefit of permanent PI can be predicted by timing of the first recurrence of syncope, but not by preimplantation factors.

Induction of heart rate and blood pressure turbulence in the electrophysiologic laboratory.

Heart rate turbulence (HRT) is a transient tachycardia and/or bradycardia that follows ventricular premature complexes (VPCs). Absent or blunted HRT is associated with a poor prognosis in patients with heart disease, but its physiology is unknown. We hypothesized that HRT might be mediated by baroreflexes following early depolarizations. We sought to induce and characterize HRT in the electrophysiologic laboratory by introducing 1 ventricular extrastimulus every 60 seconds in 23 patients who underwent invasive electrophysiologic studies. On average, HRT was characterized by an initial RR interval decrease of 38 ms occurring 3.4 seconds after early depolarization. This was followed by a transient RR interval increase of 88 ms occurring 5.4 seconds later. HRT was preceded by similar hypotensive and/or hypertensive blood pressure turbulence. Baroreflex sensitivity estimates from post-VPCs and sinus sequences were similar (12.3 +/- 10.3 vs 10.2 +/- 8.9 ms/mm Hg, p = 0.51). The failure to induce HRT was associated with a limited initial hypotensive phase of blood pressure turbulence (-7.9 vs -12.1 mm Hg, p = 0.037). Patients with structural heart disease had reduced turbulence onset and reduced turbulence slope relative to those with structurally normal hearts, although blood pressure response was similar in both groups. HRT is an inducible, transient tachycardia and/or bradycardia that likely arises from a baroreflex response to transient hypotension following VPCs. Patients with structural heart disease have blunted HRT.

Historical criteria that distinguish syncope from seizures.

OBJECTIVES: We prospectively sought evidence-based criteria that distinguished between seizures and syncope. BACKGROUND: Loss of consciousness is usually due to either seizures or syncope. There are no evidence-based historical diagnostic criteria that distinguish them. METHODS: A total of 671 patients with loss of consciousness completed a 118-item historical questionnaire. Data sets were complete for all subjects. The data set was randomly divided into two equal groups. The contributions of symptoms to diagnoses in one group were estimated with logistic regression and point scores were developed. The accuracy of the decision rule was then assessed using split-half analysis. Analyses were performed with and without inclusion of measures of symptom burden, which were the number of losses of consciousness and the duration of the history. The scores were tested using receiver-operator characteristic analysis. RESULTS: The causes of loss of consciousness were known satisfactorily in 539 patients and included seizures (n = 102; complex partial epilepsy [50 patients] and primary generalized epilepsy [52 patients]) and syncope (n = 437; tilt-positive vasovagal syncope [267 patients], ventricular tachycardia [90 patients] and other diagnoses such as complete heart block and supraventricular tachycardias [80 patients]). The point score based on symptoms alone correctly classified 94% of patients, diagnosing seizures with 94% sensitivity and 94% specificity. Including symptom burden did not significantly improve accuracy, indicating that the symptoms surrounding the loss of consciousness accurately discriminate between seizures and syncope. CONCLUSIONS: A simple point score of historical features distinguishes syncope from seizures with very high sensitivity and specificity.