Vasovagal Syncope International Study Research Articles

Sex and age differences in clinical presentation and head-up tilt test results in patients with vasovagal syncope

Abstract Background Previous evidence indicates important sex- and age-specific characteristics of vasovagal syncope (VVS), which may be relevant to diagnostic and therapeutic approaches. Purpose To investigate differences in presentation, symptoms, and head-up tilt test (HUTT) response in patients with VVS based on biological sex and age groups. Methods This study analyzed data from the HUTT registry at a tertiary syncope unit between 2017 and 2022, including adults aged 18 years or older who were diagnosed with VVS. The diagnosis was based on clinical criteria, and conformed with the latest syncope guidelines. Clinical features and head-up tilt test results were recorded and analyzed to understand the sex and age-specific characteristics of VVS. HUTT was performed using an electrically-controlled tilt table, with continuous hemodynamic monitoring, according to the Italian protocol. The type of response to HUTT was decided according to the Vasovagal Syncope International Study (VASIS) criteria, and HUTT was only considered positive if syncope occurred during the test. Results Among 1,914 eligible patients, 49% were female, and the mean age was 46.43 ± 17.77. Male participants were significantly older (44 vs 49 years of age, P<0.001), and had higher rates of diabetes mellitus (10% vs 7%) and hypertension (25% vs 19%), while female patients had a higher prevalence of anemia (24% vs 11%). There was a non-significant trend for more emergency department visits among males (7% vs 5%). Females were more likely to experience prodromal symptoms such as nausea and abdominal discomfort, typical cutaneous symptoms, and less typical prodromes like aura. Compared to males, female patients were also more likely to report specific triggers, which helps establish the diagnosis of VVS and makes avoidance of triggers possible. On the other hand, females were more likely to experience seizure-like movements, and experienced more post-syncopal symptoms. The head-up tilt test results were not significantly different based on sex (Figure 1). Younger patients were more likely to experience specific triggers and manifest prodromal symptoms, compared to older individuals, which highlights the challenges for diagnosis of VVS in older age. In contrast, younger patients with VVS were more likely to present with seizure-like movements and abnormal gaze during the VVS episode. There was a non-significant trend for higher rates of urinary incontinence during VVS among older patients. Older patients were less likely to have a cardioinhibitory response during HUTT, which confirms findings from previous studies (Figure 2). Conclusion The present study highlights the differences in the clinical presentation of VVS based on sex and age, providing valuable information for diagnosis and management of this condition. Further studies are needed to understand the mechanisms behind these differences and to develop tailored treatment plans for VVS.

Tilt table testing, methodology and practical insights for the clinic.

Tilt table testing (TTT) has been used for decades to study short-term blood pressure (BP) and heart rate regulation during orthostatic challenges. TTT provokes vasovagal reflex in many syncope patients as a background of widespread use. Despite the availability of evidence-based practice syncope guidelines, proper application and interpretation of TTT in the day-to-day care of syncope patients remain challenging. In this review, we offer practical information on what is needed to perform TTT, how results should be interpreted including the Vasovagal Syncope International Study classification, why syncope induction on TTT is necessary in patients with unexplained syncope and on indications for TTT in syncope patient care. The minimum requirements to perform TTT are a tilt table with an appropriate tilt-down time, a continuous beat-to-beat BP monitor with at least three electrocardiogram leads and trained staff. We emphasize that TTT remains a valuable asset that adds to history building but cannot replace it, and highlight the importance of recognition when TTT is abnormal even without syncope. Acknowledgement by the patient/eyewitness of the reproducibility of the induced attack is mandatory in concluding a diagnosis. TTT may be indicated when the initial syncope evaluation does not yield a certain, highly likely, or possible diagnosis, but raises clinical suspicion of (1) reflex syncope, (2) orthostatic hypotension (OH), (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT in the patient with a certain, highly likely or possible diagnosis of reflex syncope, may be to educate patients on prodromes. In patients with reflex syncope with OH TTT can be therapeutic to recognize hypotensive symptoms causing near-syncope to perform physical countermanoeuvres for syncope prevention (biofeedback). Detection of hypotensive susceptibility requiring therapy is of special value.

What is the optimal duration of the TILT after administration of 0.4 mg nitroglycerin spray?

Performing a head-up tilt test can be of great value for the diagnosis of vasovagal syncope. The European Society of Cardiology recommends a drug challenge phase duration of 15 to 20 minutes, with either Isoprenaline or Nitroglycerin administration.We sought to investigate the outcome of a ten-minute active phase with Nitroglycerin in patients suspected of vasovagal syncope and determine the percentage of loss in the positivity rate, using this short duration approach.We consecutively enrolled patients presenting with syncope undergoing the head-up tilt test (HUTT), with a clinical suspicion of vasovagal syncope between the years 2009 to 2019. The HUTT consisted of 2 successive phases: passive and active. During the passive phase, the patients were tilted at 70° for 20 minutes. If negative, the test was continued after administration of 0.4 mg sublingual Nitroglycerin. Applying the (VASIS) Vasovagal Syncope International Study classification of the vasovagal syncope international study and comparing for age and gender, positive responses were categorized into 3 types.A number of 306 patients (age = 43.5 +/−20.3; male = 140 [45.7%]) with suspected vasovagal syncope, undergoing HUTT, were enrolled in the years of 2009 to 2019. Of those, 245 (80.2%) presented a positive test, with 200 patients (82.0%) during the being positive during the active phase of the test. The results were as follows: 116 subjects (47.2%) presented with a mixed response (VASIS I), 52 (21.3%) showed a cardio inhibitory response (VASIS II), and 77 (31.5%) displayed a vasodepressor response (VASIS III). We found no relationship between the type of syncope with neither gender, nor age of the patient. Three minutes represented the median time to positivity, after Nitroglycerine administration. The time distribution showed a peak incidence appearing between minutes 3 and 5, ranging from 1 to 20 minutes. Only 3 patients tested positive after minute 10.Shortening the active phase to 10 minutes would result in a positivity rate loss of 1.5%.

Age and the Head-Up Tilt Test Outcome in Syncope Patients.

Background:The head-up tilt test (HUTT) is a useful diagnostic tool for syncope.Objectives:We sought to investigate the outcome of the HUTT in syncope patients and identify the relationship between age and different hemodynamic outcomes.Patients and Methods:In this cross-sectional study, we prospectively enrolled consecutive patients who presented with syncope and underwent the HUTT with a clinical suspicion of neurocardiogenic syncope after the exclusion of orthostatic hypotension cases. The HUTT consisted of consecutive passive and active phases. In the passive phase, the patients were tilted at 70 degrees for 20 minutes; and if negative, the test was repeated with 400 micrograms of sublingual nitroglycerin for another 20 minutes. Positive responses were classified according to the classification of the vasovagal syncope international study (VASIS) and compared for age and gender.Results:A total of 498 patients were enrolled (age = 44.93 ± 18.77 years; male = 271 [54.4%]). Overall, 291 (58.4%) patients had a positive HUTT, while 256 (88.5%) patients had a positive result during the active phase. The test results were as follows: 107 (36.7%) mixed type (VASIS I), 103 (35.3%) cardioinhibitory (VASIS IIA = 44 [15.1%]; VASIS IIB = 59 [20.2%]), and 80 (27.4%) vasodepressive (VASIS III). There was no relationship between gender and syncope type. The trend of the HUTT result significantly changed with age, and the rate of cardioinhibitory syncope decreased after middle ages (P value for trend = 0.02).Conclusions:Hemodynamic response to the HUTT was associated with age. Cardioinhibitory response became less frequent with age due to exaggerated vagal activity in the younger patients as compared with the older subjects.

Prevalence of family history in patients with reflex syncope

Reflex syncope is defined by a rapid transient loss of consciousness caused by global cerebral hypoperfusion resulting from vasodilatation and/or bradycardia attributable to inappropriate cardiovascular reflexes. A hereditary component has been suggested, but prevalence of family history may differ among subtypes of reflex syncope, as these have different autonomic responses and pathogeneses may be diverse. The present study aimed to assess the prevalence of a positive family history of syncope and cardiovascular characteristics in patients with cardioinhibitory and vasodepressor reflex syncope. Patients (n=74) were classified into subtypes of reflex syncope – cardioinhibition/asystole (Vasovagal Syncope International Study subtypes II-B [VASIS II-B], n=38) or vasodepressor (VASIS III, n=36) – using the head-up tilt test. Family history was obtained by questionnaires supplemented by interview. Patients with cardioinhibitory syncope had a mean onset of disease 8years earlier than vasodepressor patients (mean±standard deviation 14.5years±12.6 for cardioinhibitory patients compared to 22.4years±11.9 for vasodepressor patients, p<0.001). Thirty-seven (50%) of 74 probands had a positive family history with at least one relative affected with syncope, arrhythmias, known sudden unexpected death, and/or heart disease. The prevalence of a positive family history was higher in patients with cardioinhibitory syncope compared to vasodepressor syncope (24 (63%) compared to 13 (36%); p=0.02). Overall, 40 first-degree relatives (26%) and 27 second- or third-degree relatives (25%) were affected. The most frequent events in families of patients with cardioinhibitory or vasodepressor reflex syncope were severe syncope and/or arrhythmias, known sudden unexpected deaths, and heart disease. In conclusion, prevalence of familial occurrence of syncope is in agreement with previous studies. However, a high occurrence of all-cardiovascular disorders in cardioinhibitory patients may reflect shared genetic susceptibility to these diseases.

Genetic variation in the parasympathetic signaling pathway in patients with reflex syncope

Reflex syncope is defined by a self-terminating transient loss of consciousness associated with an exaggerated response of the vagal reflexes upon orthostatic challenges. A hereditary component has previously been suggested. We hypothesized that variations in genes encoding proteins mediating the vagal signaling in the heart may be involved in reflex syncope pathogenesis. We systematically resequenced the entire coding regions and flanking intron sequences in 5 genes in the cardiac post-synaptic parasympathetic signaling pathway [muscarinic acetylcholine receptor M2 (CHRM2); G-protein beta-1 subunit (GNB1); G-protein gamma-2 subunit (GNG2); potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); and potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)] in 74 patients with well-characterized reflex syncope of either cardioinhibitory [Vasovagal Syncope International Study (VASIS-IIB), N = 38] or vasodepressor (VASIS-III, N = 36) type. We identified 2 novel genetic variants (CHRM2 c.1114C>G and GNG2 c.87+34G>A) and several known variants (GNB1: c.267+14G>A, c.267+19C>T, and c.738C>T; KCNJ3: c.119A>G, c.591C>T, c.1038T>C, and c.1494T>C; KCNJ5: c. 171T>C, c.810T>G, c.834T>C, c.844C>G, c.938+7C>T, and c.938-10G>A). The minor allele frequency of the KCNJ5 c.938+7C>T variant was significantly lower in patients than in the control group (0.014 versus 0.089, P = 0.001), and the frequency of heterozygosity and homozygosity was lower in cardioinhibitory patients compared to controls. Genetic variations in genes responsible for the vagal signaling in the heart, including CHRM2, GNB1, GNG2, KCNJ3, and KCNJ5, are not major contributors to the pathogenesis of reflex syncope of vasodepressor or cardioinhibitory types.

Physiological Phenomenology of Neurally-Mediated Syncope with Management Implications

BackgroundDue to lack of efficacy in recent trials, current guidelines for the treatment of neurally-mediated (vasovagal) syncope do not promote cardiac pacemaker implantation. However, the finding of asystole during head-up tilt –induced (pre)syncope may lead to excessive cardioinhibitory syncope diagnosis and treatment with cardiac pacemakers as blood pressure is often discontinuously measured. Furthermore, physicians may be more inclined to implant cardiac pacemakers in older patients. We hypothesized that true cardioinhibitory syncope in which the decrease in heart rate precedes the fall in blood pressure is a very rare finding which might explain the lack of efficacy of pacemakers in neurally-mediated syncope.MethodsWe studied 173 consecutive patients referred for unexplained syncope (114 women, 59 men, 42±1 years, 17±2 syncopal episodes). All had experienced (pre)syncope during head-up tilt testing followed by additional lower body negative suction. We classified hemodynamic responses according to the modified Vasovagal Syncope International Study (VASIS) classification as mixed response (VASIS I), cardioinhibitory without (VASIS IIa) or with asystole (VASIS IIb), and vasodepressor (VASIS III). Then, we defined the exact temporal relationship between hypotension and bradycardia to identify patients with true cardioinhibitory syncope.ResultsOf the (pre)syncopal events during tilt testing, 63% were classified as VASIS I, 6% as VASIS IIb, 2% as VASIS IIa, and 29% as VASIS III. Cardioinhibitory responses (VASIS class II) progressively decreased from the youngest to the oldest age quartile. With more detailed temporal analysis, blood pressure reduction preceded the heart-rate decrease in all but six individuals (97%) overall and in 10 out of 11 patients with asystole (VASIS IIb).ConclusionsHypotension precedes bradycardia onset during head-up tilt-induced (pre)syncope in the vast majority of patients, even in those classified as cardioinhibitory syncope according to the modified VASIS classification. Furthermore, cardioinhibitory syncope becomes less frequent with increasing age.

RECURRENT SYNCOPE IN ELDERLY PATIENTS AND TILT TEST TABLE OUTCOME: THE ROLE OF COMORBIDITIES

Syncope is a common disorder that can lead to serious consequences in the elderly. Tilt-test is a safe, useful specific tool to investigate recurrent syncope also in the elderly. Comorbidities and medication use, widely present in elderly patients, affecting the hemodynamic response, can influence the tilt-test outcome. The aim of this study was to evaluate the influence of these confounding factors on tilt-test results in elderly patients with recurrent syncope. We included in this study a consecutive group of 87 patients > 75 years (82.1 ± 4.3 years) with unexplained syncope. They underwent passive upright tilt-test. Heart rate an blood pressure were recorded using non-invasive devices. The patients were classified according to the modified Vasovagal Syncope International Study (VASIS). Comorbidities were measured with the geriatric index of comorbidities (GIC), which is a composite score taking into account both the number of diseases and their severity as measured by Greenfield's IDS. The tilt-test was positive in 22 patients. There were no significant differences in clinical characteristics, and medication use between the tilt-test negative and positive patients, except for the GIC score (1.12 ± 0.5 vs. 2.42 ± 0.48; p = 0.001) and for a reduced number of medications in the former group (5.7 ± 3.1 vs. 8.2 ± 2.4; p = 0.001). This study suggests that comorbidities and the number of medications could influence tilt test outcome.

A novel approach to syncopal patients: association analysis of polymorphisms in G-protein genes and tilt outcome

G-proteins signal transduction pathways play a basic role in cardiovascular reflexes. We hypothesized that the predisposition to reflex-mediated syncope may be associated with genetic variations in G-protein genes. The aim of this study was to evaluate the effect of three single-nucleotide polymorphisms in G-protein genes on tilting outcome in syncopal patients. A total of 217 syncopal patients free from any other disease were genotyped and examined related to tilting results. Genotyping was performed by polymerase chain reaction followed by restriction fragment length polymorphism in gene encoding the Gs-protein alpha-subunit (polymorphism C393T), the G-protein beta 3 subunit--GNB3 (polymorphism C825T)--and for the cardiac regulator of G-protein signalling RGS2 (polymorphism C1114G). In multivariate logistic regression analysis, the homozygotes 825TT GNB3 (OR 0.37; 95% CI 0.14-0.97; P < 0.05) and body mass index (OR 0.87; 95% CI 0.78-0.97; P = 0.005) were independently associated with a lower chance of positive tilting results. No relationship was found between Vasovagal Syncope International Study type of syncope and the studied genotypes or the carriage of the polymorphic alleles. An association between tilting results and C825T GNB3 polymorphism in syncopal patients was found. The syncopal homozygotes 825TT GNB3 had a significantly lower chance of syncope during tilt testing.

Responses to Tilt test in young and elderly patients with syncope of unknown origin

The aim of the present study was to assess the cardiovascular autonomic function and responses to tilt test in young and elderly patients with syncope of unknown origin. We evaluated two groups of patients with previous unexplained syncope: 192 older subjects (112 males, 80 females, mean age 67.2 ± 6.8 years) and 188 young subjects (102 males, 86 females, mean age 25 ± 9 years). All patients underwent ambulatory electrocardiogram (ECG) monitoring, to evaluate time domain indices of heart rate variability (HRV), and head-up tilt test in the morning after an overnight fast. The responses of positive tilt test were classified using the VAsovagal Syncope International Study (VASIS) criteria: mixed (VASIS-1), cardioinhibition (VASIS-2A), severe cardioinhibition/asystole (VASIS-2B), pure vasodepression (VASIS-3). All the time-domain HRV indexes were lower in the older than in young subjects. The rate of positive responses was not different in the two groups. In elderly group the positive head-up tilt test responses showed: a pure vasodepressive response (VASIS 3) in 126 patients (65%), a mixed (VASIS-1) response in 25 patients (13%), a cardioinhibitory (VASIS-2A) response in 13 patients (7%). Only 28 (14.6%) of elderly group patients had negative head-up tilt test response. In contrast, in young group the positive head-up tilt test responses showed: 114 patients (61.2%) a mixed (VASIS-1) vasovagal response, 40 patients (22.3%) a cardioinhibitory (VASIS-2A) response, four (2.1%) patients a severe cardioinhibitory (VASIS-2B) and four (2.1%) patients a pure vasodepression (VASIS-3) response, respectively. The tilt test was negative in response in 26 young patients (12.2%). Our results confirm that the head-up tilt test may be useful in assessing unexplained syncope, since it is seen to be positive in 85% of elderly patients and 86% in young patients. In our subjects, vasodepressive response was the most frequent cause of syncope in older subjects, while vasovagal response is the commonest cause of syncope of young patients. This different behaviour in the elderly may be is explained with physiological aging, which is associated with a reduction of sympathetic-parasympathetic control on the cardiac rhythm, demonstrated by reduction in all the time domain HRV indices.

Reproducibility of tilt-table test result in patients with malignant neurocardiogenic syncope.

The indication for permanent pacemaker remains controversial in malignant neurocardiogenic syncope. A highly reproducible prolonged pause during a repeat head-up tilt-table testing may identify a subgroup of neurally mediated syncope with a prominent and consistent cardioinhibitory component. Seven patients (3 females) with a mean age of 30 years (23-44 years) were diagnosed to have malignant neurocardiogenic -syncope; all are classified according to the Vasovagal Syncope International Study as 2B type, with observed sinus pauses ranged from 3 s to 26 s of which only 1 demonstrated a reproducible sinus pause. No recurrence of syncope was clinically observed in patients during the follow-up period. Of 6 patients treated non--pharmacologically, one required a beta-blocker and none required a permanent pacemaker. Prolonged asystole manifest during head-up tilt-table testing is a poorly reproducible phenomenon and permanent pacemaker implantation in malignant neurocardiogenic syncope should not be a first line therapy.

Age and hemodynamic responses to tilt testing in those with syncope of unknown origin

ObjectivesWe sought to determine whether there are age-related differences in vasovagal syncope. BackgroundIn those with suspected vasovagal (neurocardiogenic) syncope, tilt testing demonstrates different hemodynamic responses. These responses may be age related, reflecting differing underlying pathophysiology. MethodsUsing a two-stage tilt protocol with glyceryl trinitrate (GTN) provocation, 505 consecutive syncopal patients were studied. Their baseline characteristics and hemodynamic responses during both early and tilt-induced collapse were analyzed. Hemodynamic responses were classified using the VAsovagal Syncope International Study (VASIS) criteria: mixed, cardioinhibition, severe cardioinhibition/asystole, pure vasodepression, chronotropic incompetence, and excessive heart rate rise. Multivariate regression analyses were performed to determine the associations of the baseline clinical characteristics (including age) and the tilt-induced hemodynamic responses. ResultsThirty-three patients were unable to tolerate tilt testing. Age was independently associated with distinct responses during tilt. Chronotropic incompetence was predicted by increasing age (odds ratio [OR] 1.04, p < 0.0002). Younger age predicted an excessive heart rate rise (OR 0.97, p < 0.0005). Pure vasodepression was more common in the older group (>65 years; OR 29.5, p < 0.0001), whereas severe cardioinhibition was much less common in the older age group (OR 0.18, p < 0.0001). ConclusionsThere appear to be distinct pathophysiologies underlying vasovagal syncope in different age groups. Young people appear to have excessive cardiac and autonomic responses to stress, whereas older patients appear to have a more generalized cardiovascular decline, with attenuated cardiac and autonomic responses to stress.