Tilt-induced Vasovagal Syncope Research Articles

Influence of Age on Magnitude and Timing of Vasodepression and Cardioinhibition in Tilt-Induced Vasovagal Syncope.

Cardioinhibition may diminish with age, but the changing balance of cardioinhibition and vasodepression with age has not been quantified, leaving the mechanism of vasovagal syncope (VVS) in old ageunclear. This study sought to quantify age-related changes of vasodepression and cardioinhibition in tilt-induced VVS. We studied 163 cases of tilt-induced VVS, evoked using the Italian protocol with blood pressure, heart rate, and video-electroencephalographic monitoring. Presyncope was excluded. Cardioinhibition was defined as the heart rate decrease before syncope; asystolic pauses (≥3 seconds) were divided into early and late asystole, ie, beginning early enough to or too late to be the major cause of loss of consciousness. The log-ratio method was used to quantify contributions of cardioinhibition and vasodepression, assessed in 2 10-second periods before the onset of cardioinhibition and before syncope. With increasing age, cardioinhibition decreased, ie, heart rate decreased less and more slowly near syncope (P< 0.0001), while vasodepression increased. Asystolic pauses were less frequent in the older one-half of the group than the younger one-half (26% vs 57%; P< 0.00001), but when it did, late asystole occurred more often (58% vs 15%; P<0.001). The shift toward less cardioinhibition and more vasodepression with increased age probably reflects a physiological shift in circulatory control. The weakening of cardioinhibition with age may detract from the efficacy of pacing in older patients with VVS. Cardioinhibition-vasodepression balance should be considered in pacing decisions in older subjects with VVS.

Association of Polymorphisms in Endothelin-1 and Endothelin Receptor A Genes With Vasovagal Syncope

The endothelin system may play a role in the pathogenesis of vasovagal syncope (VVS) because it is implicated in blood pressure regulation. We hypothesized that endothelin-related genetic polymorphisms might modulate susceptibility to VVS. This study aimed to evaluate the possible influence of endothelin-1 (EDN1) and endothelin receptor A (EDNRA) gene variants on the occurrence of tilt-induced VVS and autonomic nervous system activity during the head-up tilt test (HUT). Results were expressed as mean +/- SEM. In 254 patients with recurrent syncope (age 45.33+/-1.22 years, 94 males, 160 females), heart rate variability (HRV) was measured during HUT. EDN1 rs5370 G>T and EDNRA rs5333 T>C gene polymorphisms were assessed using high-resolution melting analysis. There was no statistically significant association between polymorphisms EDN1 rs5370 and EDNRA rs5333 and positivity of HUT or hemodynamic types of VVS. Patients with GT or TT genotypes at the rs5370 locus of the EDN1 had significantly higher values of high-frequency (HF) and the standard deviation of the average NN intervals at the time of the syncope, and they tended to have lower low-frequency (LF) and LF/HF ratio when compared to homozygotes (GG). No statistically significant differences were found in HRV parameters concerning the EDNRA rs5333 genotypes. Our findings suggest the potential role of EDN1 rs5370 variants in regulating autonomic nervous activity and pathogenesis of VVS.

The evolving picture of SARS-CoV-2 and COVID-19 in children: critical knowledge gaps.

<h3>Background</h3> The closed-loop stimulation (CLS) pacemaker algorithm is a system that permanently monitors the contractile state of the myocardium and converts the intrinsic information into rate regulation. The role that the CLS algorithm plays in the prevention of syncope recurrences still remains unclear. The aim of our prospective, randomised, single-blind, crossover study was to evaluate the effect of dual-chamber CLS in the prevention of syncope recurrence in patients with refractory vasovagal syncope (VVS) and a cardioinhibitory response to head-up tilt test (HUT) during a 36 months follow-up. <h3>Method sand results</h3> We studied 50 patients (mean age 53±5.1; 33 male) with the indication for permanent dual-chamber cardiac pacing for HUT-induced vasovagal cardioinhibitory syncope. They were randomised after 1 month of stabilisation period to CLS algorithm features programmed OFF or ON for 18 months each, using a crossover design. The number of syncopal and presyncopal episodes during active treatment was lower than those registered during no treatment (n syncopal episodes: 2 vs 15; p=0.007; n presincopal episodes: 5 vs 30; p = 0.004). Lead parameters remained stable over time, and there were no lead-related complications. <h3>Conclusions</h3> Based on these 36 months follow-up data, it is concluded that dual-chamber CLS is an effective algorithm for preventing syncope recurrences in healthy patients with tilt-induced vasovagal cardioinhibitory syncope.

A higher proportion of men than of women fainted in the phase without nitroglycerin in tilt-induced vasovagal syncope

PurposeVasovagal syncope (VVS) affects more women than men. We determined whether this sex ratio affects tilt table test (TTT) results.MethodsWe retrospectively studied TTT outcomes in suspected VVS. TTT consisted of supine rest, a maximum 20 min of head-up tilt without and, if nitroglycerin was needed, a further maximum 20 min after nitroglycerin administration. TTT was terminated if VVS occurred. We used binary logistic regression for the entire TTT and for each phase, with VVS as outcome and age and sex as predictors.ResultsTTT provoked vasovagal (pre)syncope in 494 out of 766 tests (64%). The proportion of men and women who fainted during the entire TTT did not differ significantly between the sexes (p = 0.13, corrected for age). A lower proportion of women than men had VVS in the phase without nitroglycerin (odds ratio 0.54; 95% confidence interval 0.37–0.79; p = 0.002, corrected for age), whereas a higher proportion of women than men fainted after nitroglycerin (odds ratio 1.58; 95% confidence interval 1.13–2.21; p = 0.008, corrected for age). These sex differences remained significant after correction for a history of orthostatic versus emotional triggers. The effect of sex on TTT outcome was closely associated with differences of blood pressure change upon tilt-up (lower in men in both TTT phases: without nitroglycerin p = 0.003; with nitroglycerin p = 0.05), but not with heart rate changes.ConclusionMen were more susceptible to induction of VVS without nitroglycerin and women after it. The unexpected findings may be due to sex-specific pathophysiological differences.

Mechanisms of tilt-induced vasovagal syncope in healthy volunteers and postural tachycardia syndrome patients without past history of syncope.

Upright tilt table testing has been used to test for vasovagal syncope (VVS) but can result in “false positives” in which tilt‐induced fainting (tilt+) occurs in the absence of real‐world fainting. Tilt+ occurs in healthy volunteers and in patients with postural tachycardia syndrome (POTS) and show enhanced susceptibility to orthostatic hypotension. We hypothesized that the mechanisms for hypotensive susceptibility differs between tilt+ healthy volunteers (Control‐Faint (N = 12)), tilt+ POTS patients (POTS‐Faint (N = 12)) and a non‐fainter control group of (Control‐noFaint) (N = 10). Subjects were studied supine and during 70° upright tilt while blood pressure (BP), cardiac output (CO), and systemic vascular resistance (SVR), were measured continuously. Impedance plethysmography estimated regional blood volumes, flows, and vascular resistance. Heart rate was increased while central blood volume was decreased in both Faint groups. CO increased in Control‐Faint because of reduced splanchnic vascular resistance; splanchnic pooling was similar to Control‐noFaint. Splanchnic blood flow in POTS‐Faint decreased and resistance increased similar to Control‐noFaint but splanchnic blood volume was markedly increased. Decreased SVR and splanchnic arterial vasoconstriction is the mechanism for faint in Control‐Faint. Decreased CO caused by enhanced splanchnic pooling is the mechanism for faint in POTS‐Faint. We propose that intrahepatic resistance is increased in POTS‐Faint resulting in pooling and that both intrahepatic resistance and splanchnic arterial vasoconstriction are reduced in Control‐Faint resulting in increased splanchnic blood flow and reduced splanchnic resistance.

Clinical features of prolonged tilt-induced hypotension with an apparent vasovagal mechanism, but without syncope.

A previous study of electroencephalography (EEG) changes with syncope led to a finding that some young patients develop prolonged periods of tilt-induced hypotension, but they do not lose consciousness. The present study aim was to compare patterns of hemodynamic changes, measures of duration, and sweating between these patients and patients with tilt-induced vasovagal syncope. In an observational study, qualitative changes in hemodynamic parameters were compared between patients with prolonged hypotension (n = 30) and with syncope (n = 30). To demonstrate that periods of hypotension far-exceed the typical presyncope period, several parameters were used to compare the durations of events between groups. Differences in sweating patterns were explored. Parallels in hemodynamic changes were present in both groups suggesting similar vasovagal mechanisms. Patients with prolonged hypotension had longer durations of hypotension (165 ± 44 versus 57 ± 13 s, p < 0.001), diminished cardiac output (109 ± 38 versus 32 ± 9 s, p < 0.001), and EEG slowing (85 ± 31 versus 9 ± 4 s, p < 0.001) compared to patients with syncope. While all patients generated an increase in sweat rate, those with hypotension only developed a robust sweat response that always preceded the plateau in hypotension compared to 14 (47%) patients with syncope who developed an increase in sweating prior to syncope, p < 0.001. Similarities are present among hemodynamic changes with prolonged hypotension and with tilt-induced vasovagal syncope, suggesting a possible vasovagal mechanism for prolonged hypotension. If true, understanding why some individuals develop a vasovagal response that does not culminate in rapid syncope may help to elucidate the physiologic underpinnings of the vasovagal reflex.

Tilt-induced vasovagal syncope and psychogenic pseudosyncope: Overlapping clinical entities

In the article “Tilt-induced vasovagal syncope and psychogenic pseudosyncope: Overlapping clinical entities” by H. Blad et al.,1 there is one error in the risk calculation of having both conditions (VVS …

Time- and frequency-domain analysis of beat to beat P-wave duration, PR interval and RR interval can predict asystole as form of syncope during head-up tilt

To seek possible differences in short-period temporal RR interval, P-wave and PR interval dispersion and spectral coherence in patients with a head-up tilt test positive for vasovagal syncope with or without prolonged asystole, severe symptoms and at high risk of trauma.We retrospectively reviewed 5 min ECG and blood pressure recordings obtained at baseline, at rest and during head-up tilt in 40 patients diagnosed as having recurrent vasovagal syncope confirmed at a head-up tilt test. We analysed autoregressive spectral power for all the ECG-derived variables, focusing on temporal P-wave and PR interval dispersion indexes as well as their spectral coherence calculated on the same 5 min recordings at rest and during tilt.ECG recordings obtained during tilt before syncope showed significantly lower P → PR spectral coherence and higher RR standard deviations in patients with tilt-induced asystole than in those without (0.567 ± 0.097 versus 0.670 ± 0.127, p: 0.010 and 84 ± 36 versus 46 ± 22 ms2, p < 0.0001). Differences in the RR standard deviations persisted also on the last hundred beats (−100) (113 ± 54 versus 34 ± 17 ms2, p < 0.0001). Multiple regression analysis identified a significantly negative association between the maximum RR intervals and P → PR coherence at rest (β: −0.3, p < 0.05) and positive association with RR−100 standard deviation during tilt-induced syncope (β: 0.621, p < 0.001).P → PR spectral coherence could be used to assess the risk of prolonged asystole in patients with tilt-induced vasovagal syncope as well as as a possible surrogate for tilt-testing during these patients’ follow-up.

The Role of the Baroreflex in TiltTableTesting: Outcome and Type of Response.

The purpose of this study was to better understand the role of the baroreflex in tilt-induced vasovagal syncope (VVS). The role of the baroreflex in tilt-induced VVS remains controversial. The authors hypothesized that: 1)patients with positive tilt table test (TTT) results have greater baroreflex gain (BRG) compared with patients with negative TTT results; and 2) patients with tilt-induced asystole have greater BRG compared with patients without asystole. Using the sequence method, BRG measurements were obtained in 438 consecutive patients undergoing TTT. Two hundred sixty-eight patients (61%) had positive TTT results (mean age 50 ± 21 years; 34% men), and 170 patients (39%) had negative TTT results (mean age 48 ± 21 years; 35% men). Mean BRG was significantly higher in patients with positive TTT results compared with those with negative TTT results (12.9 ± 6.0ms/mmHg vs. 11.5 ± 6.0ms/mmHg; p= 0.01). Among the 268 patients with positive TTT results, 23 (9%) had more than 3 s of asystole (mean age 37 ± 17; 30% men), and 245 patients had a mixed vasodepressor or cardioinhibitory response without asystole (mean age 51 ± 17 years; 34% men). Mean BRG was greater in patients with tilt-induced asystole (>3 s) compared with patients without asystole (15.3 ± 5.9ms/mmHg vs. 12.7 ± 5.9ms/mmHg; p= 0.03). The results of this study demonstrate that baseline BRG was higher in patients with positive TTT resultscompared with those with negative TTT results, with greater values noted in patients with tilt-induced asystole (>3 s) compared with those without asystole.

Spotlight on the December 8 Issue

#### Notable in Neurology This issue features an article evaluating whether diffusion tensor imaging can predict epileptogenicity of tubers in patients with pediatric tuberous sclerosis complex undergoing epilepsy surgery and another investigating the clinical spectrum and distinguishing features of adenylate cyclase 5–related dyskinesia and genotype–phenotype relationship. A third article examines the association between enlarged perivascular spaces and small diffusion-weighted lesions in intracerebral hemorrhage. ### Tilt-induced vasovagal syncope and psychogenic pseudosyncope: Overlapping clinical entities Vasovagal syncope and psychogenic pseudosyncope (PPS) may occur together. The authors examined this complex phenotype and compared its presenting features with those of isolated vasovagal syncope. …

Tilt-induced vasovagal syncope and psychogenic pseudosyncope: Overlapping clinical entities.

To describe the combination of tilt-induced vasovagal syncope (VVS) and psychogenic pseudosyncope (PPS) and aid its clinical recognition. We identified people with tilt-induced VVS/PPS from 2 tertiary syncope referral centers. For each case, 3 controls with tilt-induced VVS were selected at random from the same center. Clinical characteristics were compared between both groups adjusting for multiple comparisons. Of 1,164 tilt-table tests, 23 (2%) resulted in VVS/PPS; these 23 cases were compared with 69 VVS controls. VVS and PPS coincided more often than chance would predict: 2% vs 0.6%, p < 0.001. Typical VVS prodromes and triggers were reported in all people with VVS/PPS and in controls with VVS. Attack frequency was significantly higher in the VVS/PPS (2 per month, range 0.1-60) than in the VVS group (0.25 per month, range 0.02-4; p < 0.001). Delayed recovery of consciousness was more frequently reported in the VVS/PPS group (likelihood ratio [+LR] 8.14, 95% confidence interval [CI] 3.94-16.84), as well as episodes without prodromes (+LR 5.57, 95% CI 2.53-12.26), atypical triggers (+LR 5.00, 95% CI 2.04-12.24), eye closure (+LR 3.75, 95% CI 1.68-8.35), and apparent loss of consciousness >1 minute (+LR 2.86, 95% CI 1.98-4.13). VVS/PPS presents with a complex phenotype. High attack frequency, delayed recovery of consciousness, apparent loss of consciousness >1 minute, ictal eye closure, atypical triggers, and the absence of prodromes may serve as indicators that PPS coincides with VVS.

Symptoms, Signs, and EEG Changes During Reflex Syncope

Investigators at Leiden University Medical Centre, The Netherlands, studied the symptoms, video data of signs, and EEG changes during tilt-induced vasovagal syncope in 69 subjects, age range 12-84 years (mean 46 years).

The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes

Syncope is defined as transient loss of consciousness as a result of cerebral hypoperfusion. Electroencephalography during syncope shows either a 'slow-flat-slow' or a 'slow' pattern. The first is believed to denote more severe hypoperfusion. Although the diagnosis of vasovagal syncope relies primarily on history taking, there is limited evidence regarding the relative importance of various clinical features, and none that relate them to the severity of electroencephalographic changes. The aim of this investigation was to study symptoms, signs and electroencephalographic changes with a 1 s resolution using electroencephalography and video data in 69 cases of tilt-induced vasovagal syncope. The main finding was that flattening of the electroencephalograph indicated more profound circulatory changes: the 'slow-flat-slow' group had a lower minimum blood pressure, longer maximum RR-interval, contained more cases with asystole and had a longer duration of loss of consciousness than the 'slow' group. Second, we describe a range of signs, including some that have rarely been reported in syncope, e.g. oral automatisms. Third, signs occurred at different rates depending on electroencephalographic flattening, suggesting a classification of syncopal signs. Type A signs (e.g. loss of consciousness, eye opening and general stiffening) develop during the first slow phase, stay present during flattening and stop in the second slow phase. Type B (particularly myoclonic jerks) occur when the electroencephalograph is slow but not flat: their abolition with electroencephalographic flattening suggests dependence on cortical activity. Type C signs (making sounds, roving eye movements and stertorous breathing) occur only in the flat phase, whereas type D (dropping the jaw and snoring) may occur either in slow or flat phases. In conclusion, our findings provide a detailed assessment of clinical symptoms in relation to electroencephalographic (EEG) changes during tilt-induced syncope.

The semiology of tilt-induced psychogenic pseudosyncope

To provide a detailed semiology to aid the clinical recognition of psychogenic pseudosyncope (PPS), which concerns episodes of apparent transient loss of consciousness (TLOC) that mimic syncope. We analyzed all consecutive tilt-table tests from 2006 to 2012 showing proven PPS, i.e., apparent TLOC had occurred without EEG changes or a decrease in heart rate (HR) or blood pressure (BP). We analyzed baseline characteristics, video data, EEG, ECG, and continuous BP measurements on a 1-second time scale. Data were compared with those of 69 cases of tilt-induced vasovagal syncope (VVS). Of 800 tilt-table tests, 43 (5.4%) resulted in PPS. The majority (74%) were women. The median duration of apparent TLOC was longer in PPS (44 seconds) than in VVS (20 seconds, p < 0.05). During the event, the eyes were closed in 97% in PPS but in only 7% in VVS (p < 0.0001). A sudden head drop or moving down the tilt table was more common in PPS than in VVS (p < 0.01), but jerking movements occurred more frequently in VVS (p < 0.0001). In PPS, both HR and BP increased before and during apparent TLOC (p < 0.0001). PPS is clinically distinct from VVS and can be diagnosed accurately with tilt-table testing and simultaneous EEG monitoring. Compared with VVS, eye closure during the event, long periods of apparent TLOC, and high HR and BP are highly specific for PPS. Improved understanding of the semiology of PPS as a clinical entity is vital to ensure accurate diagnosis.

The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, single-blind, crossover study

BackgroundThe closed-loop stimulation (CLS) pacemaker algorithm is a system that permanently monitors the contractile state of the myocardium and converts the intrinsic information into rate regulation. The role that the...

Sympathoadrenal imbalance and beta-blockers revisited

Our understanding of the pathophysiology of vasovagal syncope (VVS) has improved substantially in last 2 decades; however, the exact mechanism that leads to an episode of VVS has remained elusive. The dominant model holds that an episode of VVS has several phases. The initial phase of sympathetic stimulation occurs in response to a stressor, which may either be orthostatic, physical, or emotional. This sympathetic phase is often compensatory and results in both increased heart rate and increased myocardial contractility. The hyperdynamic contraction of the myocardium results in the activation of intramyocardial ganglionic plexi, triggering a parasympathetic counter response, and ultimately causes bradycardia, arterial vasodilatation, hypotension, cerebral hypoperfusion, and syncope. Prior studies have demonstrated that the initial sympathetic phase of VVS is characterized by an increase in circulating levels of both epinephrine and norepinephrine, with the increase in epinephrine levels proportionately higher than the increase in norepinephrine levels, especially in patients with a predominant vasodepressor component. Higher epinephrine levels may partially explain the vasodepressor component of VVS, via activation of the beta2-adrenergic receptors, contributing to peripheral arterial vasodilatation. In this issue of HeartRhythm, Benditt et al report on the age-related differences in epinephrine and norepinephrine levels during tilt-induced VVS. In a cohort of 29 patients, 12 patients were aged 40 years and older and 17 were younger than 40 years. They found that baseline epinephrine and norepinephrine levels and the baseline epinephrine/norepinephrine ratio (Epi/NE) in the 2 age groups were similar. They also found that epinephrine levels increased 12.5to 14.6-fold from the baseline to the onset of syncope, while norepinephrine levels increased to a much lower degree (1.8to 2.0-fold). However, the Epi/NE ratio was higher in younger patients at 2 minutes (1.02 vs 0.40; P 1⁄4 .11) of the upright tilt and at the onset of syncope (2.60 vs1.64; P 1⁄4 .03). On the basis of these observations, they suggest that these findings may, in part, explain why beta-blockers tended to be less effective in younger patients in randomized trials. They conclude with a call for a randomized trial addressing

Age-dependence of relative change in circulating epinephrine and norepinephrine concentrations during tilt-induced vasovagal syncope

Although vasovagal syncope (VVS) is preceded by a surge of circulating catecholamines (epinephrine [Epi] and norepinephrine [NE]) of adrenal/renal and synaptic origin, prevention of VVS with β-adrenergic blockade has been ineffective except in "older" VVS patients. We hypothesized that age-related differences of β-blocker effect may be due in part to differences in the relative magnitudes of Epi and NE release during an evolving faint, specifically, greater Epi/NE ratio in younger fainters compared to older patients. To assess this hypothesis, we measured changes in Epi/NE ratios in younger (<40 years) vs older (≥40 years) patients during head-up tilt-table test-induced VVS. The study comprised 29 patients (12 patients ≥40 years [mean 56 ± 10.7 years] and 17 patients <40 years mean 25 ± 5.7 years]) with recurrent suspected VVS in whom 70° head-up tilt testing reproduced symptoms. Arterial Epi and NE concentrations were measured at baseline (supine), 2 minutes of head-up tilt, and syncope. Baseline Epi and NE concentrations and the Epi/NE ratio did not differ in younger and older groups (Epi: 90 ± 65 pg/mL vs 70 ± 32 pg/mL; NE: 226 ± 122 pg/mL vs 244 ± 183 pg/mL). However, Epi/NE ratio increased to a greater extent in younger fainters during head-up tilt and tended to be greater in younger patients at both 2 minutes (<40: 1.02 ± 1.29 vs ≥40: 0.40 ± 0.27, P = .11) and at symptoms (<40: 2.6 ± 1.26 vs ≥40: 1.6 ± 0.71, P = .03). At symptoms, Epi/NE ratio ≥2.5 was observed in 9 of 17 younger patients vs 1 of 12 older patients (P = .02). Epi/NE ratios tend to be greater in younger fainters, a finding that may account in part for the observation that β-blocker therapy is less effective in reducing VVS susceptibility in younger individuals.

Lack of association between genetic polymorphisms affecting sympathetic activity and tilt-induced vasovagal syncope

Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested. Since predisposition to fainting during orthostatic challenge may be associated with genetic variations, we sought to explore the role of genetic polymorphisms affecting sympathetic nervous system function in the susceptibility to tilt-induced vasovagal syncope. We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope. The analysed polymorphisms were Arg492Cys ( ADRA1A gene), Ser49Gly and Arg389Gly ( ADRB1), Arg16Gly and Gln27Glu ( ADRB2), 825C/T ( GNB3), –1021C/T ( DBH) and S/L ( SLC6A4). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found. None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients.

Endothelin system polymorphisms in tilt test-induced vasovagal syncope

Genetics may be involved in the pathophysiology of vasovagal syncope. The 3A/4A polymorphism of the EDN1 gene affects the expression of endothelin-1, and the H323H T/C polymorphism of the EDNRA gene encoding for the endothelin type A receptor has been associated with cardiovascular pathologies. As the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of these genetic variants in influencing tilt-induced vasovagal syncope. We recorded the cardiovascular parameters of 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test; 58 (54%) fainted. In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07-5.26) and 2.41 (1.05-5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant. In conclusion, the 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothhelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing.

Endothelin system polymorphisms in tilt test-induced vasovagal syncope

As the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of endothelin system polymorphisms in influencing tilt-induced vasovagal syncope. We evaluated 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test. All subjects were genotyped for the 3A/4A polymorphism of the EDN1 gene and the H323H T/C polymorphism of the EDNRA gene. Fifty-eight patients (54%) fainted. In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07-5.26) and 2.41 (1.05-5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant. The 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing.