The role of clinical assessment and electrophysiology study in Brugada syndrome patients with syncope.

BACKGROUND: Cardiogenic syncope in Brugada syndrome (BrS) increases the risk of major events. Nevertheless, clinical differentiation between cardiogenic and vasovagal syncope can be challenging. We characterized the long-term incidence of major events in a large cohort of BrS patients who presented with syncope. METHODS: From a total of 474 patients, syncope was the initial manifestation in 135 (28.5%) individuals (43.9 ±â€¯13.9 years, 71.1% male). The syncope was classified prospectively as cardiogenic, vasovagal, or undefined if unclear characteristics were present. Clinical, electrocardiographic, genetic, and electrophysiologic features were analyzed. Cardiogenic syncope, sustained ventricular arrhythmias, and sudden death were considered major events in follow-up. RESULTS: In 66 patients (48.9%), the syncope was cardiogenic; in 51 (37.8%), vasovagal and in 18 (13.3%); undefined. The electrophysiology study (EPS) inducibility was more frequent in patients with cardiogenic syncope and absent in all patients with undefined syncope (28 [53.8%] vs 5 [12.2%] vs 0 [0%]; P < .01). During follow-up (7.7 ±â€¯5.6 years), only patients with cardiogenic syncope presented major events (16 [11.9%]). Among patients with inducible EPS, 7 (21.2%) presented major events (P = .04). The negative predictive value of the EPS for major events was 92.4%. The incidence rate of major events was 2.6% person-year. Parameters associated with major events included cardiogenic syncope (hazard ratio [HR] 6.3; 95% CI 1.1-10.4; P = .05), spontaneous type 1 electrocardiogram (HR 3.7; 95% CI 1.3-10.5; P = .01), and inducible EPS (HR 2.8; 95% CI 1.1-8.8; P = .05). CONCLUSIONS: An accurate syncope classification is crucial in BrS patients for risk stratification. In patients with syncope of unclear characteristics, the EPS may be helpful to prevent unnecessary implantable cardioverter defibrillators.

Novel functional advanced echocardiography for the assessment of myocardial mechanics in children with neurocardiogenic syncope - a blinded prospective speckle tracking head-up tilt-table challenge study.

BACKGROUND: Data on left ventricular (LV) function in patients with neurocardiogenic syncope (NS) is conflicting in adults and lacking in children. The aim of this study was to analyze LV myocardial performance in children with NS at rest and during head-up tilt-table (HUTT) testing. METHODS: This is the first study to combine HUTT and speckle-tracking echocardiography (STE) in children with NS. 43 consecutive normotensive pediatric patients with NS (mean age 13.9 ± 2.6 years, 51% female) and 41 sex- and age-matched healthy controls were included in the study. The study groups consisted of 21 patients with a positive HUTT reaction (HUTT+) and 22 with a negative HUTT reaction (HUTT-). STE was used to analyze peak systolic LV myocardial strain and strain rate. RESULTS: Conventional echocardiographic parameters were similar in all analyzed groups. When compared to healthy controls, children with NS had depressed levels of circumferential strain rate (p = 0.032) and significantly depressed longitudinal strain rate (p <  0.001) at rest. Interestingly, during HUTT testing LV global strain and strain rate were similar in both groups. LV strain rate was lowest in HUTT+ followed by HUTT- and control subjects both at rest and during HUTT. CONCLUSIONS: Resting LV longitudinal strain rate is attenuated in children with NS, especially in those with a positive HUTT response. This is further evidence that NS patients feature altered cardiac mechanics rendering them prone to vasovagal perturbations that can ultimately result in collapse. TRIAL REGISTRATION: Witten/Herdecke University ethics committee clinical study number: UWH-73-2014.

Rationale for the Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects Trial (POST5).

BACKGROUND: Vasovagal syncope (VVS) is a common problem associated with a poor quality of life, which improves when syncope frequency is reduced. Effective pharmacological therapies for VVS are lacking. Metoprolol is a ß-adrenergic receptor antagonist that is ineffective in younger patients, but may benefit older (≥40 years) VVS patients. Given the limited therapeutic options, a placebo-controlled clinical trial of metoprolol for the prevention of VVS in older patients is needed. STRUCTURE OF STUDY: The POST5 is a multicenter, international, randomized, placebo-controlled study of metoprolol in the prevention of VVS in patients ≥40 years old. The primary endpoint is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive metoprolol 25 to 100 mg BID or matching placebo, and followed up for 1 year. Secondary end points include syncope frequency, presyncope, quality of life, and cost analysis. Primary analysis will be intention to treat, with a secondary on-treatment analysis. POWER CALCULATIONS: A sample size of 222, split equally between the groups achieves 85% power to detect a hazard rate of 0.3561 when the event rates are 50% and 30% in the placebo and metoprolol arms. Allowing for 10% dropout, we propose to enroll 248 patients. IMPLICATIONS: This study will be the first adequately powered trial to determine whether metoprolol is effective in preventing VVS in patients ≥40 years. If effective, metoprolol may become the first line pharmacological therapy for these patients.

The Value of Tilt Testing and Autonomic Nervous System Assessment.

Tilt testing for the investigation of syncope was introduced in 1986. Since then, it has propagated worldwide as a routine test to determine the cause of transient loss of consciousness when that event has not been diagnosed by history, including that of a witness, physical examination, supine and erect blood pressures, and 12-lead electrocardiogram. Tilt testing allows reproduction of syncope with monitoring of physiologic parameters including electrocardiogram, beat-to-beat blood pressure, electroencephalogram, and middle cerebral artery blood-flow velocity. As a result, much has been learned about syncope.

Autosomal dominant vasovagal syncope: clinical features and linkage to chromosome 15q26.

OBJECTIVE: To establish the occurrence of an autosomal dominant form of vasovagal syncope (VVS) by detailed phenotyping of multiplex families and identification of the causative locus. METHODS: Patients with VVS and a family history of syncope were recruited. A standardized questionnaire was administered to all available family members and medical records were reviewed. Of 44 families recruited, 6 were suggestive of autosomal dominant inheritance. Genome-wide linkage was performed in family A using single nucleotide polymorphism genotyping microarrays. Targeted analysis of chromosome 15q26 with microsatellite markers was implemented in 4 families; 1 family was too small for analysis. RESULTS: Family A contained 30 affected individuals over 3 generations with a median onset of 8 to 9 years. The other families comprised 4 to 14 affected individuals. Affected individuals reported typical triggers of VVS (sight of blood, injury, medical procedures, prolonged standing, pain, frightening thoughts). The triggers varied considerably within the families. Significant linkage to chromosome 15q26 (logarithm of odds score 3.28) was found in family A. Linkage to this region was excluded in 2 medium-sized families but not in 2 smaller families. Sequence analysis of the candidate genes SLCO3A1, ST8SIA2, and NR2F2 within the linkage interval did not reveal any mutations. CONCLUSIONS: Familial VVS, inherited in an autosomal dominant manner, may not be rare and has similar features to sporadic VVS. The chromosome 15q26 locus in family A increases the susceptibility to VVS but does not predispose to a particular vasovagal trigger. Linkage analysis in the remaining families established likely genetic heterogeneity.

Update on the role of pacemaker therapy in vasovagal syncope and carotid sinus syndrome.

Vasovagal syncope (VVS) and carotid sinus syndrome (CSS) are related, neurally mediated disorders with different clinical features and treatment implications. Pacemaker intervention studies in both syndromes are hampered by a dearth of randomized, controlled (particularly with placebo) studies, unfortunate premature termination of studies, and variation in both the clinical presentation and cardiovascular profile of patients enrolled. Given this relatively limited evidence base, pacing therapy in VVS should be reserved for older sufferers with relatively frequent symptoms and spontaneous asystole documented during real-life monitoring. The long term course of patients paced for vasovagal syncope needs clarification, both in terms of symptom and device-related burden, while a comprehensive health economic evaluation of the costs and benefits of such an invasive approach for this usually benign condition is essential. It will also be important to determine the efficacy of closed loop stimulation pacing in an adequately powered study, including a comparison with standard pacing. Pacing should be considered in those with unexplained syncope with reproduction of symptoms during a cardio-inhibitory or mixed response to carotid sinus massage (asystole >3 s), though the evidence base for this recommendation is firmly in the consensus rather than pragmatic randomized controlled trial camp. Patients presenting with unexplained falls and drop attacks, particularly where injuries are prominent and where patients cannot give a clear account of their fall ("I just ended up on the floor, didn't slip or trip"), should also be considered for pacing. Pacing is not recommended for the vasodepressor sub-type of CSS.

Tilt testing is more cost-effective than implantable loop recorder monitoring as a means of directing pacing therapy in people with recurrent episodes of suspected vasovagal syncope that affect their quality of life or present a high risk of injury.

OBJECTIVE: To assess the cost-effectiveness of implantable loop recorders (ILRs) and tilt testing (TT) to direct pacing therapy in people with recurrent episodes of transient loss of consciousness that are adversely affecting their quality of life or represent a high risk of injury and are suspected to be vasovagal. DESIGN: Decision analytical modelling was used to estimate the costs and benefits of diagnostic testing including the costs and benefits of treatment for several clinically important arrhythmias following diagnosis. SETTING: A UK National Health Service and personal social services perspective was taken. PATIENTS: People with recurrent episodes of transient loss of consciousness that are adversely affecting their quality of life or represent a high risk of injury and which are suspected to be vasovagal. INTERVENTIONS: The diagnostic test strategies compared were TT alone, TT followed by ILR (if TT 'negative'), ILR alone and no further testing. MAIN OUTCOME MEASURES: Benefits measured using quality-adjusted life years and incremental cost-effectiveness ratios (ICER) are reported. RESULTS: The ICERs for TT alone, ILR alone and TT followed by ILR were £5960, £24 620 and £19 110, respectively, compared with no testing. ILR alone was extendedly dominated by the other strategies, meaning that it is never the most cost-effective option. Sensitivity analysis found that the cost-effectiveness estimates were robust despite the areas of uncertainty identified in the evidence and assumptions used to inform the model. CONCLUSIONS: TT alone is likely to be the most cost-effective strategy in this population.

What is the optimal duration of tilt testing for the assessment of patients with suspected postural tachycardia syndrome?

AIMS: The aim of this study is to define the optimal duration of tilt testing for the assessment of patients with suspected postural tachycardia syndrome (POTS). METHODS AND RESULTS: This was a case-control study. Cases were identified retrospectively from a database of patients referred with orthostatic intolerance (OI). All met the diagnostic criteria for POTS. Controls were enrolled prospectively. All subjects underwent tilting to 70 degrees for 40 min if tolerated. Continuous monitoring was provided by a Finometer. Analysis of responses to tilting was performed on 28 cases and 28 controls. The mean age in the case group was 23.6 and in the control group was 26.2. The majority was female in both groups (cases = 4F:3M, controls = 2F:1M). All cases met the criteria for POTS within 7 min of orthostasis. No controls demonstrated a sustained tachycardia. The prevalence of vasovagal syncope (VVS) was 36% in cases vs. 7% in controls (P = 0.02) and 25% in the remaining patients (n = 233) on the OI database (P = 0.259). CONCLUSION: A 10 min tilt will diagnose POTS in the majority of patients. It will not, however, be sufficient to identify the overlap that exists between POTS and VVS. The optimal duration of tilt testing in patients suspected of POTS is 40 min.

Assessment of cardiovascular autonomic function.

Autonomic assessment has played an important role in elucidating the role of the autonomic nervous system in diverse clinical and research settings. The techniques most widely used in the clinical setting entail the measurement of an end-organ response to a physiological provocation. The non-invasive measures of cardiovascular parasympathetic function involve the analysis of heart rate variability while the measures of cardiovascular sympathetic function assess the blood pressure response to physiological stimuli. Prolonged tilt-table testing, with or without pharmacological provocation, has become an important tool in the investigation of a predisposition to neurally mediated (vasovagal) syncope. Frequency domain analyses of heart rate and blood pressure variability, microneurography, occlusion plethysmography, laser Doppler imaging and flowmetry, and cardiac sympathetic imaging are currently research tools but may find a place in the clinical assessment of autonomic function in the future.

Cardiovascular reactivity score for the assessment of dysautonomia in familial Mediterranean fever.

OBJECTIVE: The aim of this study was to assess the presence of dysautonomia, as manifested in abnormal cardiovascular reactivity, in patients with familial Mediterranean fever (FMF). METHODS: Fifty-five consecutive patients with FMF and 23 age- and sex-matched healthy controls were evaluated. Cardiovascular reactivity was studied: (1) using recordings of blood pressure (BP) and heart rate (HR) during 10 min of recumbence and 30 min of head-up tilt test to identify clinical endpoints and (2) during tilt-test, identifying parameters acting as independent predictors of FMF reactivity and enabling computation of a cardiovascular reactivity score (CVRS). RESULTS: Clinically, vasovagal reaction, postural tachycardia syndrome, and/or orthostatic hypotension were observed in ten patients (18.1%). Utilizing a derived equation, the group average CVRS in FMF was 5.83+/-1.78 (healthy group -7.60+/-5.41) ( P=<0.0001). A CVRS of >3.25 was associated with FMF, with 98% sensitivity and 100% specificity. CONCLUSION: A very high percentage of FMF patients exhibit abnormal cardiovascular reactivity which is clinically occult but can be detected on autonomic challenge and application of the CVRS.

Pathophysiology and management of neurocardiogenic syncope.

OBJECTIVE: To discuss the physiologic mechanisms underlying neurocardiogenic syncope in the context of several different management strategies. PATHOPHYSIOLOGY: Neurocardiogenic syncope or the "common faint" is variously called neurally mediated hypotension, vasovagal syncope, or vasodepressor syncope. It is the most common type of syncope. The pathophysiology of neurocardiogenic syncope is complex and not completely elucidated. Individuals susceptible to neurocardiogenic syncope are unable to maintain the adaptive neurocardiovascular responses to upright posture for prolonged periods. These patients tend to have a modest reduction in central blood volume, which is aggravated by upright posture. It is often noted in individuals receiving sympathetic blocking agents and vasodilator drugs for hypertension, elderly patients receiving tranquilizers, patients with anemia, and individuals with tran- sient reductions in blood volume such as those that occur after a brisk diuresis or blood donation. The classic syncopal episode often is preceded by a constellation of prodromal symptoms several seconds before the event that may include nausea, headache, diaphoresis, dizziness, chest pain, palpitations, dyspnea, and paresthesia. MANAGEMENT: Head-up tilt testing has become the diagnostic study of choice for the identification of patients with neurocardiogenic syncope. Therapeutic options include general measures such as volume expansion; pharmacologic approaches such as beta-adrenergic receptor blockade, anticholinergic agents, selective serotonin reuptake inhibitors, methylxanthines, and alpha agonists; and invasive methods such as placement of a dual-chamber cardiac pacemaker.

[Assessment of the changes in autonomic nervous function during head up tilt test in syncopal patients using spectral analysis of heart rate variability].

OBJECTIVE: To study the pathological mechanism of vasovagal syncope, spectral analysis of heart rate variability was used to evaluate the changes of autonomic function during head up tilt test in patients with unexplained syncope. METHODS: 27 patients with recurrent episodes of unexplained syncope underwent 70 degrees head up tilt test. Spectral analysis was used to assess the changes in autonomic function before tilt testing, immediately after tilting, just before the occurrence of syncope or at the end of the test, during the syncope period or at the end of the test and after testing in supine rest. At the same time, haemodynamic changes were recorded. Spectral power in very low frequency (VLF, 0.003 - 0.04 Hz), low frequency (LF, 0.04 - 0.15 Hz) and high frequency (HF, 0.15 - 2.00 Hz) were computed with Fast Fourier Transform analysis, and LF and HF were normalized: LF norm = 100 x LF/(TP-VLF) and HF norm = 100 x HF/(TP-VLF). RESULTS: 12 patients (mean age 40 +/- 10 years) showed a negative response and 15 patients (mean age 37 +/- 9 years) showed a positive response. Both systolic and diastolic blood pressure decreased in all the patients [(118.00 +/- 10.42-->81.00 +/- 12.36) mm Hg, P < 0.01 and (76.00 +/- 8.40-->52.00 +/- 10.95) mm Hg, P < 0.01] and heart rate decreased in 8 patients (53%). No significant difference in all the indices of spectral analysis was observed in supine position between the subjects with positive and negative test results. LF norm in both the groups did not alter during the entire tilt procedure. The decreased HF norm and increased LF/HF persisted throughout head up tilt test in the negative patients. In the positive patients, similar patterns of changes were observed before the occurrence of positive symptoms, and during the occurrence of the symptoms. HF norm abruptly rose (10.47 +/- 4.04-->32.95 +/- 10.48) and obviously exceeded that before tilt testing (23.44 +/- 4.20-->32.95 +/- 10.48, P < 0.05) and LF/HF dropped (3.28 +/- 0.39-->1.07 +/- 0.31, P < 0.01). At supine rest just after test, all the indices in both groups came back. CONCLUSIONS: In the supine position, autonomic function is similar between positive and negative subjects. Positive patients have a different pattern of response to the tilting test. The pathological mechanism leading to vasovagal syncope appears to be related with the abrupt and excessive increase of vagal activity.

Pacing to prevent vasovagal syncope.

Patients with frequent vasovagal syncope have markedly poor quality of life and are often resistant to treatment with standard pharmacologic approaches. Vasovagal syncope is due to combinations of bradycardia and hypotension. There is accumulating evidence that many of these patients may respond to permanent cardiac pacing. Several controlled open-label studies suggest that about half of paced patients no longer faint, and most of the rest are improved. At this point, we do not know the role of placebo, and specific pacing modes in this improvement are not known. Ongoing trials will clarify how to select patients and how best to pace them.

Vasovagal syncope: prevalence and presentation. An algorithm of management in the aviation environment.

Vasovagal syncope can occur in any individual, given sufficient provocation, and probably half the population suffers at least one episode during life. Often it occurs in youth and may occur in clusters. Usually there is a history of a previous episode. Prodromal symptoms include nausea sweatiness and a sensation of warmth. Diagnosis is by careful history and tilt testing. The false positive rate for passive tilt is 13% and the true positive rate is about 70% including use of nitroglycerine. A classical history and a positive tilt test obviate the need for further investigation in clinical practice, but in the context of aviation, it is wise to seek the small possibility of intermittent rhythm and/or conduction disturbance as an alternative explanation for the episode. It is, therefore, reasonable to carry out a Holter recording and exercise electrocardiogram, perhaps also echocardiography. No treatment is of much benefit, although many agents, including beta blocking drugs, have been used. Some patients have undergone permanent dual chamber pacing with some favourable results. Explanation and reassurance is important. From the licensing point of view, following investigation after an attack, consideration may be given to restricted certification with regular follow-up. Review with investigation after an event free interval, arbitrarily after 2 years, may permit full certification. Malignant vasovagal syncope with no warning of impending attack should disbar.

Assessment of autonomic function at rest and during tilt testing in patients with vasovagal syncope.

This study evaluated autonomic nervous system function in 30 patients with syncope and a positive tilt test result, 20 with a negative test result, and 20 healthy controls. Indexes of heart rate variability were measured during the intervals immediately before and after tilt, while all subjects were asymptomatic, and over a 24-hour period. There were no significant differences among the groups in any of the indexes of heart rate variability over the 24-hour period. In patients with a positive tilt result, tilting caused a decrease in low-frequency (LF) and high-frequency (HF) bands, although the LF/HF ratio did not significantly change. In patients with a negative tilt result there was a decrease in the HF band but no other significant changes. In the controls there was an increase in the LF band and LF/HF ratio and a decrease in the HF band. Our findings showed that patients with vasovagal syncope have no chronic differences from normal subjects in autonomic nervous system activity, but that these patients respond differently to the orthostatic stimulus.