A randomized study of tilt test angle in patients with undiagnosed syncope.

BACKGROUND: A widely used tilt test protocol involves passive head-up tilt followed by tilt with isoproterenol infusion if necessary. Little is known about the effects of passive tilt angle and duration, duration of isoproterenol infusion or hemodynamic diagnostic criteria. OBJECTIVES: To assess whether tilt angle and duration of isoproterenol infusion affected test outcomes in patients with undiagnosed syncope. PATIENTS AND METHODS: Two hundred one syncope patients (87 men, age 45+/-20 years, median five faints) were randomly assigned to undergo 60 degrees versus 80 degrees tilt for 45 min, then, if necessary, to receive isoproterenol 30 ng/kg/min for 20 min or less. Positive tests ended in presyncope or syncope. RESULTS: Overall, 49% and 71% of patients fainted at 60 degrees and 80 degrees, respectively (P=0.002). In the drug-free stage, 27% and 50% of patients fainted at 60 degrees and 80 degrees, respectively (P=0.0005). In the 119 patients who received isoproterenol, there was no significant difference in the probability of a positive isoproterenol test at 60 degrees and 80 degrees, respectively (31% compared with 43% of exposed patients, P=0.25). Symptoms developed in adults during drug-free tilt linearly with time at both 60 degrees and 80 degrees at 0.6% and 1.1%/min, respectively, while symptoms during isoproterenol tilt reached an asymptote after about 10 min. Rate-systolic pressure products of 7000 mmHg/min and 9000 mmHg/min best distinguished positive from negative passive and isoproterenol stages, respectively. CONCLUSIONS: The positive yield of passive tilt tests is higher at 80 degrees and increases linearly with the duration of tilt. A subsequent 10 min isoproterenol infusion maximizes positive yield. Evidence-based outcome criteria accurately distinguish negative from positive tilt tests.

Usefulness of clinical factors in predicting outcomes of passive tilt tests in patients with syncope.

Pretest patient selection affects the outcome of many diagnostic tests; this may be true for tilt-table tests. We assessed the impact of patient age, sex, and symptom burden on the outcome of passive tilt tests. Two hundred one patients with idiopathic syncope (87 men, aged 45 +/- 20 years, median 5 fainting spells each) underwent passive, drug-free tilt tests for 45 minutes. Positive tests were defined as those ending in clinically reminiscent presyncope or syncope. Seventy-eight patients (39%) had a positive tilt test. Patients had a wide range of symptom burden, having a median 5 syncopal spells (interquartile range [IQR] 2.5 to 17.5) over a median 52.5 months (IQR 12 to 180) with a median frequency of 0.17 spells/month (IQR 0.042 to 0.67). None of these measures of symptom burden predicted tilt-test outcome (p = 0.33 to 0.46). In contrast, the age of the patient strongly predicted tilt-test outcome. The likelihood of a positive test was 75% in 36 patients < 25 years old and 31% in 165 patients > or = 25 years of age (p < 0.0001, chi-square for 2 x 5 table). Younger patients also fainted more quickly: patients < 25 years old fainted within 22 minutes of tilt and reached a clearly asymptotic value, whereas the likelihood of a positive tilt in patients > or = 25 years old increased linearly with time, and did not reach an asymptote. Measures of symptom burden do not predict test outcome, and younger patients are more likely to faint during passive tilt testing.

The relationship between health-related quality of life and frequency of spells in patients with syncope.

Chronic syncope has a wide range of symptom burden, and anecdotal data suggest substantial but variable physical and psychosocial morbidity. We hypothesized that health-related quality of life (HRQL) is impaired in syncope patients and the degree of impairment is proportional to syncope frequency. The EuroQol EQ-5D was completed by 136 patients (79 female and 57 male) with mean age 40 (SD = 17) prior to assessment. HRQL was substantially impaired in syncope patients compared to population norms in all five dimensions of health measured by the EQ-5D. In patients with six or more lifetime syncopal spells there was a significant (P < 0.001) negative relationship between the frequency of spells and overall perception of health, which was not evident in those who had a history of less than six lifetime spells. These relationships were maintained after controlling for comorbid conditions.

Cost-utility analysis of pacemakers for the treatment of vasovagal syncope.

Dual-chamber pacing is a promising treatment for patients with very frequent vasovagal syncope, but its cost utility is unknown. We report that the incremental cost per quality-adjusted life-year gained is $13,159 Canadian dollars (about $8,600 US dollars), and therefore this pacemaker therapy for vasovagal syncope has a favorable cost-utility ratio.

Origins of heart rate variability: relationship of heart rate burst morphology to work duration and load.

We are developing a lexicon of specific heart period changes, or lexons, that recur frequently and whose physiological meaning can be read into ambulatory electrocardiogram (ECG). The transient, reversible "burst" of tachycardia induced by exercise initiation can also be seen on ambulatory ECG. We hypothesized that burst morphology depended on the work that preceded it and on baroreceptor activation. Ten subjects with mean age 38 yr (range 17-69 yr) underwent two protocols of semisupine cycling in which load and duration were varied. Burst duration increased with longer cycling times (median values of 18.0, 25.5, and 23.7 s with 1, 3, and 5 s of cycling, respectively; P = 0.033). Burst shape as assessed by heart period exponential decay constant and burst magnitude did not change. To assess the impact of workload, subjects cycled for 5 s at loads of 0, 25, 50, and 75 W. No significant differences were seen in burst duration, burst magnitude, or burst shape. Tachycardia preceded hypotension by 4.6 +/- 2.2 s, which is inconsistent with baroreceptor involvement in the onset of burst tachycardia. Because burst morphology is a nearly quantal response to the initiation of exercise, the presence of a burst on an ambulatory ECG implies the onset of exercise.

Origins of heart rate variability. Inducibility and prevalence of a discrete, tachycardic event.

BACKGROUND: We propose that heart period sequences are linearly organized, like sentences, and that there is a lexicon of recurrent, similarly shaped transient structures like words. Each word (or lexon) has a characteristic physiological basis. One potential lexon is the transient, reversible tachycardia that is induced by exercise initiation under laboratory conditions. We hypothesized that this lexon was inducible and observable on ambulatory ECGs of most or all subjects, was morphologically similar in both induced and detected bursts, and shared a plausible origin in both circumstances. METHODS AND RESULTS: Ten healthy subjects (mean age, 36 years) underwent a protocol in which subjects rolled themselves from supine to lateral decubitus positions and back. Transient tachycardias ("bursts") were seen in 36 of 40 rollovers. Bursts were characterized by an initial monoexponential heart period decay (K=0.39+/-0.23 s-1), a maximum heart period decrease of 277+/-109 ms after 10.8+/-4.5 seconds, and a subsequent return to baseline 23.3+/-10.8 seconds after roll initiation. The roll-induced bursts were detected with 97% sensitivity and 99% specificity with a search algorithm that incorporated morphological parameters. In 24-hour ambulatory ECGs of 10 healthy subjects (mean age, 38 years; range, 17 to 69 years), 117+/-59 bursts were detected. Induced and detected bursts were similar in most morphological parameters. Finally, many bursts occurred at night, when rolling over also occurs. CONCLUSIONS: Bursts are inducible, transient tachycardias that occur clinically and constitute a lexon with an understandable physiology.

Statistical issues encountered in the comparison of health-related quality of life in diseased patients to published general population norms: problems and solutions.

The objectives of this study were (1) to illustrate the statistical problems encountered when comparing health-related quality of life (HRQL) measured by the Medical Outcome Study Short Form-36 (SF-36) in a diseased group to general population norms, and (2) to define age- and gender-standardized dichotomous indicator variables for each health concept and show that these indicator variables facilitate comparisons between the diseased sample and the general population. Our "diseased" group consisted of 136 sequentially consenting patients referred to the syncope clinic for assessment and treatment. Participants completed the SF-36 questionnaire before undergoing diagnostic testing. General population norms for the SF-36 are available from the responses of 2474 participants in the National Survey of Functional Health Status, conducted in 1990 in the United States. Comparison of the SF-36 in a diseased sample with general population norms is difficult, owing to skewed and unusual distributions in both groups. In addition, making comparisons within age and gender strata is difficult if the within strata sample size is small. We propose a dichotomous indicator variable for each health concept that classifies an individual as having impaired health if he or she scored lower than the 25th percentile for the appropriate age and gender general population strata. By definition, the prevalence of impaired health in the general population is 25% for all eight health concepts. Comparison between the eight health-concept variables is easy because the population norm is the same for each of them. These indicator variables are age and gender adjusted, so that even if the sample did not have the age and gender distribution as the general population, comparisons can still be made with the value of 25.

Electroencephalographic findings during presyncope and syncope induced by tilt table testing.

OBJECTIVE: To determine electroencephalographic (EEG) changes occurring during syncope induced by headup tilt table testing. DESIGN: Prospective observational study. SETTING: Calgary General Hospital Syncope Clinic, Calgary, Alberta. PATIENTS: Eighteen patients with a history of recurrent syncope who developed syncope while undergoing diagnostic isoproterenol tilt table testing. INTERVENTIONS: Continuous EEGs were recorded in 18 sequentially consenting patients while they underwent diagnostic headup tilt table testing. MAIN RESULTS: Patients developed presyncope after 2.6 +/- 2.4 mins and syncope after 3.7 +/- 2.5 minutes. Systolic blood pressure dropped from 117 +/- 17 mmHg to 65 +/- 9 mmHg, and heart rate dropped from 124 +/- 26 beats/min to 65 +/- 27 beats/min. Fourteen patients developed presyncope, while five developed syncope without appreciable presyncope. Abnormal EEGs were recorded in 13 of 14 patients during presyncope and in 18 of 18 patients during syncope. No patients developed EEG abnormalities before the onset of presyncope, and the proportion of patients with EEG abnormalities gradually increased throughout presyncope. During presyncope, theta and delta wave slowing, and background suppression were noted in eight of 14, nine of 14 and one of 14 patients, respectively. During syncope, theta and delta wave slowing, and background suppression were noted in nine of 18, 11 of 18 and six of 18 patients, respectively (not significant versus presyncope). There were strikingly abrupt changes in the EEG rhythm within 15 s of the transition to syncope in 14 of 18 patients. Six patients developed new theta wave slowing, 11 developed new delta wave slowing, and seven developed background suppression. No epileptiform activity was recorded. CONCLUSIONS: Both presyncope and syncope induced by tilt testing are associated with EEG abnormalities, and no single EEG pattern is pathognomonic of either. The transition from presyncope to syncope is marked by abrupt EEG changes.

Effect of dual-chamber pacing with automatic rate-drop sensing on recurrent neurally mediated syncope.

We tested the hypotheses that a dual-chamber pacemaker that paces when intrinsic rate drops abruptly would reduce the number of syncopal spells and improve the quality of life in patients with highly recurrent neurally mediated syncope. Twelve patients with highly frequent neurally mediated syncope and at least 1 syncopal spell after tilt testing received dual-chamber pacemakers with automatic rate-drop sensing. The pacemakers were implanted 17+/-26 months after tilt testing, and the patients then were followed for 12+/-2 months. We compared the time to the first recurrence of syncope, syncope frequency, and quality of life for the 2 periods between tilt testing and pacemaker implantation, and between implantation and last follow-up. Only 6 of 12 patients fainted after pacemaker insertion. The median time to syncope recurrence before and after pacing was 7 days and 5.3 months, respectively. The geometric mean frequency of faints before and after pacing was 5.0 spells/month (95% confidence interval 2.7 to 9.2) and 0.30 spells/month (95% confidence interval 0.2 to 0.4), p <0.001. After 6 months the mean perception of health on the 100-point EuroQol scale rose from 55 to 82 (p = 0.003), and the general health perception on the SF-36 scale rose from 51 to 72 (p = 0.005). Permanent dual-chamber pacing with automatic rate-drop sensing in patients with highly frequent syncope is associated with a marked reduction in the likelihood of syncope and a marked improvement in quality of life.

Comparison of patients with syncope of unknown cause having negative or positive tilt-table tests.

Many patients without an identified cause of syncope have negative tilt tests. We hypothesized that many of these might be falsely negative tilt tests. If so, then patients with negative and positive tilt tests should have similar pretest clinical characteristics, post-test probabilities of remaining free of syncope, and similar risk factors for syncope recurrence after the tilt-table test. Demographic characteristics and historic features were compared between 153 syncope patients with a positive tilt test, and 74 syncope patients with a negative tilt test and no obvious cause of syncope. Patients with negative and positive tests had similar numbers of syncopal spells, durations of symptoms, frequency of spells, and peak heart rate during tilt test, but patients with negative tests were older (48 +/- 19 vs 39 +/- 20 years). The actuarial probabilities of remaining free of syncope were very similar, with 2-year risks of syncope of 41% and 37% in patients with negative and positive tests, respectively. The regression coefficients of risk factors predicting syncope recurrence were similar for both populations, and the confidence intervals of all regression coefficients decreased when the populations were combined. The outcome of tilt testing did not predict the clinical outcome of patients. Patients with syncope and either negative or positive tilt tests share many pretest and post-test clinical characteristics, suggesting that they may be part of the same population.

Timing of first recurrence of syncope predicts syncopal frequency after a positive tilt table test result.

OBJECTIVES: This study sought to determine whether the time to first recurrence of syncope after a positive isoproteremol-tilt table test result accurately predicts the eventual frequency of syncope. BACKGROUND: Both patient care and future clinical trials involving patients with neuromediated syncope will require a simple measure that reflects the frequency of syncope. The time from tilt table testing to the first recurrence of syncope might be such a measure. METHODS: A cohort of 46 patients with syncope, in a university outpatient clinic, who had at least one syncopal spell after a positive isoproterenol-tilt table test result were followed up for up to 6.5 years (mean [+/-SD] 48 +/- 14 months). The time from tilt table testing to the first recurrence of syncope was correlated. RESULTS: A total of 40 of 46 patients had more than one recurrent spell, with a median of eight recurrent spells. The time to the first syncopal spell predicted the frequency of spells with r = -0.79 (p < 0.001), whereas the time to the second spell predicted the frequency with r = -0.92 (p < 0.001). Patients who fainted within 1 month of tilt testing had a geometric mean frequency of 1.35 spells/month (95% confidence limits 0.49, 3.74) compared with patients who fainted 1 to 24 months after testing (0.12 spells/months; 95% confidence limits 0.07 to 0.18, p < 0.001). Finally, the frequency of syncopal spells bore no relation to the duration of follow-up. CONCLUSIONS: The time to the first recurrent spell predicts the frequency of syncopal spells after a positive tilt table test result, and the instantaneous risk of syncope is constant.

Isoproterenol tilt-table testing in patients with syncope and structural heart disease.

We studied 55 patients with syncope and structural heart disease using both tilt-table testing and electrophysiologic studies. Although sustained ventricular tachycardia was found in 21 of 55 patients (38%), and neuromediated syncope in 18 of 51 patients (35%), only 16% of patients with ventricular tachycardia had a positive tilt-table test.

Effect of beta blockers on the time to first syncope recurrence in patients after a positive isoproterenol tilt table test.

Isoproterenol-headup tilt table testing provides a diagnosis of neuromediated syncope in many patients who faint. The involvement of beta-adrenoceptor stimulation in the provocation of syncope suggests that beta blockers might chronically prevent syncope. To assess this, a cohort of 153 syncope patients (age 39 +/- 20 years) underwent baseline assessment of demographic variables, symptomatic burden, and hemodynamic and clinical responses to tilt testing. Fifty-two patients then received beta blockers, and 101 did not receive drug therapy. The primary outcome was the time to the first recurrent syncopal spell. Actuarial survival analysis was used. Syncope recurred in 17 of 52 patients who received beta blockers and in 28 of 101 patients who were untreated. The actuarial probability of remaining free of syncope was similar in both groups. For example, the probability of remaining free of syncope 12 months following the tilt test was 0.72 in both populations. Thus, treatment with beta blockers may not have a significant effect in preventing syncope recurrence following a positive tilt test.

Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope.

BACKGROUND: Recent work with head-up tilt-table testing has suggested that many patients with syncope may have recurrent neurally mediated episodes of bradycardia, hypotension, or both. The purpose of this study was to determine how to identify patients at high risk of a recurrence of neuromediated syncope after a positive isoproterenol/tilt-table test. METHODS AND RESULTS: A cohort of 101 drug-free patients in a university hospital outpatient clinic with syncope and a positive isoproterenol/tilt-table test underwent baseline assessment of demographic variables, symptomatic burden, and hemodynamic and clinical responses to tilt testing. The primary outcome measure was the time to the first recurrent syncopal spell. The actuarial probabilities of remaining syncope free after 1 and 2 years were 72% and 60%, respectively. Multivariate proportional hazards analysis demonstrated that the most powerful predictor of a recurrence of syncope was the logarithm of the number of preceding syncopal spells (P<.001). Other predictive variables included the duration of syncopal symptoms, tilt test symptomatic outcome, and trough heart rate. The probability of a recurrence of syncope also varied with the logarithm of the frequency of preceding spells (P=.008). The median frequency of pretest spells was 0.3/month; after the tilt test, the median frequency dropped approximately 90% to 0.03 per month. CONCLUSIONS: The risk of a recurrence of syncope after a positive tilt-table test can be predicted with simple pretest and intratest variables.

Antiarrhythmic activity of quinine in humans.

BACKGROUND: Quinine is the diastereomer of quinidine. In dogs, it has similar effects on conduction time but does not prolong epicardial repolarization time or ventricular refractoriness. It has antiarrhythmic effects in both cats and dogs. We assessed the antiarrhythmic potential of quinine in suppressing ventricular arrhythmias in humans. METHODS AND RESULTS: Patients underwent open-label, dose-ranging trials of quinine with daily doses of 600, 1200, and 1800 mg in a twice-daily dosing regimen. In 17 patients with frequent spontaneous ventricular ectopy, oral quinine suppressed arrhythmia in 11 of 12 patients who finished the study and was not tolerated by 4 patients, and 1 patient withdrew from the study. The mean effective daily dosage was 927 mg, the mean effective trough serum level was 11 mumol/L (range, 4 to 17 mumol/L), and the half-life was 20 +/- 7 hours. In a second open-label, dose-ranging trial in 10 patients with inducible ventricular tachycardia and reduced left ventricular systolic function (left ventricular ejection fraction, 35 +/- 16%), quinine suppressed inducibility of ventricular tachycardia in 3 of 10 patients. At a basic pacing cycle length of 500 milliseconds, ventricular effective refractory period was prolonged (279 +/- 21 versus 247 +/- 10 milliseconds, quinine versus drug free, P = .003). In the remaining patients, ventricular tachycardia cycle length was prolonged (373 +/- 48 versus 253 +/- 30 milliseconds, quinine versus drug free, P < .001). The corrected QT interval was not prolonged. CONCLUSIONS: Quinine is an effective and convenient antiarrhythmic drug for the suppression of ventricular arrhythmias in humans.