Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope.

We measured changes in transcranial Doppler ultrasound (TCD) and near infrared spectroscopy (NIRS) during 70° upright tilt in patients with recurrent vasovagal syncope (VVS, N = 20), postural tachycardia syndrome (POTS, N = 20), and healthy controls (N = 12) aged 15-27 years old. VVS was included if they fainted during testing within 5-15 min of upright tilt. We combined TCD and NIRS to obtain estimates of percent change in the cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow velocity (CBFv), and oxygen extraction fraction (OEF). Over the course of 10 min of upright tilt, CBFv decreased from a baseline of 70 ± 5 to 63 ± 5 cm/sec in controls and 74 ± 3 to 64 ± 3 cm/sec in POTS while decreasing from 74 ± 4 to 44 ± 3 cm/sec in VVS CMRO2 was unchanged in POTS and controls during tilt while OEF increased by 19 ± 3% and 15 ± 3%, respectively. CMRO2 decreased by 31 ± 3% in VVS during tilt while OEF only increased by 7 ± 3%. Oxyhemoglobin decreased by 1.1 ± 1.3 µmol/kg brain tissue in controls, by 1.1 ± 1.3 µmol/kg in POTS, and 11.1 ± 1.3 µmol/kg in VVS CBFv and CMRO2 fell steadily in VVS during upright tilt. The deficit in CMRO2 in VVS results from inadequate OEF in the face of greatly reduced CBF.

Increased (18)F-fluorodeoxyglucose accumulation in bilateral adrenal glands of the patients suffering from vasovagal reaction due to blood vessel puncture.

OBJECTIVE: The purpose of the study was to evaluate the hypothesis that patients having a vasovagal reaction (VVR) after blood vessel puncture show increased FDG accumulation in bilateral adrenal glands. METHODS: Over the past 8 years, 26 patients experienced a VVR after blood vessel puncture following intra-venous injection of FDG at our institution. Of the 26 patients, 16 underwent multiple-occasion FDG-PET/CT scans while suffering a VVR at only one examination. All 16 patients had no morphological abnormality in the adrenal glands on FDG-PET/CT and follow-up examination. For the 16, we retrospectively reviewed the FDG-PET/CT scan with respect to the adrenal glands and compared the result to that for the FDG-PET/CT scan of the same patient when there was no VVR event. We used both visual analysis and semi-quantitative analysis employing either maximum standardized uptake value (SUVmax) or adrenal-to-liver (A/L) SUVmax ratio. RESULTS: On visual analysis of the FDG-PET/CT with VVR, accumulations in both of the adrenal glands was judged positive, defined as higher than the hepatic accumulation, in 84 % of the cases. The SUVmax in the right adrenal gland was 2.79 ± 0.69 with VVR and 1.92 ± 0.33 without VVR; this value in the left adrenal gland was 3.07 ± 0.71 with VVR and 2.05 ± 0.39 without. Mean SUVmax of both adrenal glands was 2.93 ± 0.66 with VVR and 1.98 ± 0.35 without. The A/L SUVmax ratio in the right adrenal gland was 1.02 ± 0.26 with VVR and 0.69 ± 0.11 without; this value in the left was 1.11 ± 0.23 with VVR and 0.74 ± 0.15 without. The mean A/L SUVmax ratio of both adrenal glands was 1.06 ± 0.24 with VVR and 0.72 ± 0.13 without. Each parameter with VVR was significantly higher than that without. For the two adrenal glands, the mean SUVmax with VVR was 48 % higher than that without VVR. CONCLUSIONS: We confirmed the hypothesis that patients having a VVR after blood vessel puncture show increased FDG accumulation in their bilateral adrenal glands. This may reflect hyper-metabolism of the adrenal glands in synthesizing and secreting catecholamine.

Relationship between human evolution and neurally mediated syncope disclosed by the polymorphic sites of the adrenergic receptor gene α2B-AR.

The objective of this study was to clarify the effects of disease on neurally mediated syncope (NMS) during an acute stress reaction. We analyzed the mechanism of the molecular interaction and the polymorphisms of the alpha-2 adrenoreceptor (α2B-AR) gene as the potential psychiatric cause of incentive stress. We focused on the following three genotypes of the repeat polymorphism site at Glu 301-303 in the α2B-AR gene: Glu12/12, Glu12/9, and Glu9/9. On the basis of our clinical research, NMS is likely to occur in people with the Glu12/9 heterotype. To verify this, we assessed this relationship with the interaction of Gi protein and adenylate cyclase by in silico analysis of the Glu12/9 heterotype. By measuring the difference in the dissociation time of the Gi-α subunit twice, we found that the Glu12/9 heterotype suppressed the action of adenylate cyclase longer than the Glu homotypes. As this difference in the Glu repeat number effect is thought to be one of the causes of NMS, we investigated the evolutionary significance of the Glu repeat number. Glu8 was originally repeated in simians, while the Glu12 repeats occurred over time during the evolution of bipedalism in humans. Taken with the Glu12 numbers, NMS would likely become a defensive measure to prevent significant blood flow to the human brain.

Assessment of therapeutic biomarkers in the treatment of children with postural tachycardia syndrome and vasovagal syncope.

BACKGROUND: Postural tachycardia syndrome and vasovagal syncope are common causes of orthostatic intolerance in children. The supplementation with water, or salt, or midodrine, or ß-blocker was applied to children with postural tachycardia syndrome or vasovagal syncope. However, the efficacy of such medication varied and was not satisfied. This review aimed to summarise the current biomarkers in the treatment of the diseases. DATA SOURCES: Studies were collected from online electronic databases, including OVID Medline, PubMed, ISI Web of Science, and associated references. The main areas assessed in the included studies were clinical improvement, the cure rate, and the individualised treatment for postural tachycardia syndrome and vasovagal syncope in children. RESULTS: Haemodynamic change during head-up tilt test, and detection of 24-hour urinary sodium excretion, flow-mediated vasodilation, erythrocytic H2S, and plasma pro-adrenomedullin as biological markers were the new ways that were inexpensive, non-invasive, and easy to test for finding those who would be suitable for a specific drug and treatment. CONCLUSION: With the help of biomarkers, the therapeutic efficacy was greatly increased for children with postural tachycardia syndrome and vasovagal syncope.

Low iron storage in children with tilt positive neurally mediated syncope.

BACKGROUND: The mechanisms under neurally mediated syncope (NMS) are not fully understood. This study aimed to assess the level of storage iron in children with different hemodynamic patterns in head-up tilt test. METHODS: Altogether 210 children (11.31±2.49 years) with syncope or pre-syncope treated between May 2008 and September 2010 were studied prospectively. Following history taking and physical examination, their levels of hemoglobin (Hb), hematocrit (Hct) and serum ferritin were measured. RESULTS: In the 210 children, 162 (77.1%) had NMS and 48 (22.9%) had syncope due to other causes. In the 162 children with NMS, 98 children were subjected to positive tilt test. The level of serum ferritin was significantly lower in the 98 children with NMS (P<0.001). The comparison of levels of Hb, Hct and mean cell volume (MCV) displayed no significant difference between the two groups. Reduced iron storage (serum ferritin <25 ng/mL) was found to be more prevalent in children with NMS (63% vs. 20%, P<0.001). Prevalence of iron deficiency was also significantly higher in children with NMS than in children with syncope due to other causes (27% vs. 6%, P=0.003). CONCLUSIONS: In head-up tilt test positive children with NMS, the level of serum ferritin should be evaluated. Low storage iron may be one of the underlying mechanisms of NMS.

[Clinical features and changes of 5-hydroxytryptamine in children with vasovagal syncope].

OBJECTIVE: To investigate clinical features of childhood vasovagal syncope (VVS) and the possible relationship between changes of plasma and platelet 5-hydroxytryptamine (5-HT) and childhood VVS. METHOD: Forty-one children who were diagnosed as VVS because of positive head-up tilt test (HUTT) in Capital Institute of Pediatrics were enrolled as HUT-positive group, while 36 healthy children as control group. Clinical features of all children were analyzed, and blood samples of all children were obtained. Plasma and platelet 5-HT was measured by enzyme-linked immunosorbent assay (ELISA). RESULT: (1) The mean age of 41 VVS children was (10.5 +/- 1.8) years, and there were more girls than boys with the boys to girls ratio of 1:1.4. (2) Presyncopal symptoms occurred in 33 patients (80.4%), among whom dizziness had a high rate: 78.8%. (3) Commonly, there were some provocation factors before syncope, among which long-time standing was the most common one with the rate of 91.7%. (4) The mean time of positive response in BHUT and SNHUT were (20.6 +/- 8.6) minutes and (5.0 +/- 2.2) minutes, respectively. Duration of syncope was shorter than 5 minutes. (5) HUTT positive response included vasodepressor type with the rate of 61.0%, cardioinhibitory type with 14.6%, and mixed type with 24.4%. (6) There were no significant differences in baseline heart rate, systolic blood pressure and diastolic blood pressure between VVS children and healthy children. And it was the same among different types of VVS children. (7) There were no significant differences in plasma 5-HT between VVS group of baseline or HUTT-positive and control group [(27.51 +/- 1.32) microg/L vs.(27.28 +/- 2.48)microg/L, t = 0.518, P = 0.606; (27.51 +/- 1.32) microg/L vs.(28.05 +/- 1.40) microg/L, t = 2.044, P = 0.167]. There were no significant differences in platelet 5-HT concentration between VVS group of baseline and control group [(82.30 +/- 6.06) 10(9) ng/L vs. (79.88 +/- 5.79) 10(9) ng/L, t = 1.788, P = 0.780].(8) HUTT-positive platelet 5-HT concentration of VVS children was significantly higher than baseline value [(97.90 +/- 6.59) 10(9) ng/L vs. (82.30 +/- 6.06) 10(9) ng/L, t = 11.26, P = 0.00]. CONCLUSION: There were no significant changes in plasma 5-HT in children with VVS during baseline, syncope or pre-syncope, which suggests that plasma 5-HT might not be valuable for the prediction of syncope trigger. However, platelet 5-HT of VVS children was obviously higher during syncope and presyncope, which suggests that central serotonergic system might be involved in the pathogenesis of VVS.

Endothelin system polymorphisms in tilt test-induced vasovagal syncope.

INTRODUCTION: 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. MATERIALS AND METHODS: We recorded the cardiovascular parameters of 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test; 58 (54%) fainted. RESULTS: 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. CONCLUSION: 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.

Myocardial adrenergic innervation in patients with vasovagal syncope measured with 123I-MIBG uptake.

BACKGROUND: Data about biochemical abnormalities (catecholamines) during vasovagal syncope (VVS) are available, but adrenergic myocardial structural damage may be hypothesized as well. AIM: To study the global and regional adrenergic myocardial innervations in patients with VVS that was shown by head-up tilt table testing. PATIENTS AND METHODS: Fifteen adult patients with VVS were studied. The age of patients was 44+/-18 years (17-73), nine were female and six were male. According to the tilt test results, five patients had cardioinhibition, six patients had vasodepressor syncope and four patients suffered from mixed-type VVS. Ischemic heart diseases were excluded by normal Tc-MIBI rest-stress dipyridamol single-photon emission computed tomography (SPECT) results. A control group was formed from six healthy adult volunteers. To investigate cardiac sympathetic innervations 250-370 MBq iodine-123 meta-iodobenzylguanidine (I-MIBG) was used. Fifteen minutes after the intravenous administration of I-MIBG early, and 2-3 h later, delayed planar myocardial and tomographic (SPECT) scintigraphies were performed. The heart-to-mediastinum count ratio (H/M) was calculated for both early and delayed images, together with the decay-corrected change rates. The regional I-MIBG uptake was visualized on SPECT slices and polar map images. The regional uptake was considered pathological below 50% compared with normal uptake sites. RESULTS: Delayed H/M ratios significantly depended on group (analysis of variance: P=0.005), whereas early H/M values did not. Although the decay-corrected myocardial MIBG uptake increased in time in controls, less wash-in or even wash-out could be observed in the VVS groups; however, difference from the controls was significant only in the vasodepressor group (Dunnett's t-test: P<0.05). All patients had regional I-MIBG uptake deficit in different regions. CONCLUSION: In our patients with VVS, global I-MIBG deficit was present frequently, and all patients had regional adrenergic nerve function deficit. These alterations may play a role in causing clinical symptoms and have importance in staging and treatment planning.

Genetic insight into syncopal tilted population with severe clinical presentation.

UNLABELLED: An impairment of cardiovascular reflexes may be the result of functional alterations in the G proteins intracellular signaling produced by functional genes' polymorphisms. The aim was to evaluate the relationships between single nucleotide polymorphisms in genes encoding G-proteins signaling pathways and syncopal patients with severe clinical manifestation. METHODS AND RESULTS: From 307 syncopal patients free from any other diseases 83 (27%) had at least one malignant episode of syncope with a significant injury as fractures. There was 1.9 malignant spells per patient. All patients were tilted and genotyped by polymerase chain reaction followed by restriction fragment length polymorphism method. 74 healthy volunteers with negative history of syncope constituted the control group were also genotyped. Following polymorphisms were detected: C393T in gene encoding the alfa-subunit of Gs-protein (GNAS1), C825T of gene for G-protein beta 3 subunit (GNB3) and C1114G for the gene of cardiac regulator of G-protein signaling (RGS2). We found an association with lower risk of malignant syncope in positive tilting patients during passive phase of the test compared to NTG-enhanced (OR 0.38; 95% CI 0.15-0.95; P=0.04). No difference between healthy controls and patients in the alleles frequency was found (P>0.05). Neither the 393T allele of GNAS1 and 825T allele of GNB3 nor 1114G allele of RGS2 was associated with enhanced risk of severe clinical manifestation (P>0.05). CONCLUSIONS: The studied single nucleotide polymorphisms of genes encoding G-proteins signaling pathways seem to be not connected with the severe clinical manifestation of syncope.

Síncope neurocardiogênica e exercício / Neurocardiogenic syncope and exercise

A síncope neurocardiogênica acomete, na grande maioria das vezes, pessoas jovens, aparentemente normais, e que, com a recorrência de sintomas, passam a apresentar limitações quanto às atividades de vida diária e profissional. O tratamento convencional, realizado com bases nas medidas gerais(aumento da ingestão de líquidos, evitar situações desencadeantes e outras), e drogas, como beta-bloqueadores, fludrocortisona e inibidores de recaptação de serotonina, nem sempre é eficaz em diminuir a frequência e a intensidade dos episódios sincopais. Cada vez mais, buscam-se, em todo o mundo, medidas de caráter não farmacológico para minimizar a ocorrência de sintomas. Nesse aspecto, e com base na fisiopatologia das síncopes neuromediadas, recursos como o Tilt training e o treinamento físico apresentam-se como alternativa para abordagem, visto à maior aceitabilidade dos mesmos por parte dos pacientes, relutantes muitas vezes em fazer uso de medicação. Esse artigo busca, através de extensa revisão bibliográfica, discorrer sobre os diversos aspectos do exercício, relacionado-os à fisiopatologia e ao tratamento da síncope neurocardiogênica

[Neurohumoral mechanisms for vasovagal syncopes. Part I]. / Mechanizmy neurohumoralne omdlen wazowagalnych. Czesc I.

Vasovagal syncope is defined as a reflex loss of consciousness related to reaction to various stimuli as orthostatic stress, pain or emotions connected with loss of muscle postural tone. The aetiology of this disorder is still unknown. The imbalance between the parts of autonomic nervous system and other homeostasis-related systems as renin-angiotensin-aldosterone system, peptides as endothelin, neuropeptide Y, vasopressin, adrenomedullin and cAMP, adenosine and AMP can play an important role in the development of vasovagal syncope. In the first part of the paper the authors describe the mechanisms involved in the development of vasovagal reaction, pathophysiology of the head-up tilt test and the role of autonomic nervous system.

[Neurohumoral mechanisms for vasovagal syncopes. Part II]. / Mechanizmy neurohumoralne omdlen wazowagalnych. Czesc II.

Vasovagal syncope is defined as a reflex loss of consciousness related to reaction to various stimuli as orthostatic stress, pain or emotions connected with loss of muscle postural tone. In the second part of the paper the authors describe the possible role of the particular neurohumoral factors and autonomic nervous system in the development of vasovagal syncope. The studies on the involvement of neurohumoral factors in vasovagal syncope can play a key role in a more precise evaluation of affected patients, long term prophylaxis against syncopal events and may contribute to development of more reliable diagnostic tests.

Tissue oximetry for the diagnosis of neurally mediated syncope.

This study examined the potential clinical contribution of noninvasive brain and skeletal muscle oximetry as a diagnostic aid in neurally mediated syncope. Tilt table testing was performed in 15 patients with a history of syncope and 9 healthy volunteers. Spatially resolved reflectance near-infrared spectroscopy was used to examine regional oxyhemoglobin saturation in the frontal cerebral cortex and pectoral muscle. During upright tilt, syncope occurred in four patients. Each episode was associated with bradycardia, hypotension, and brain oxygen desaturation of > 20% from the supine reference baseline, while the largest desaturation in nonsyncopal patients was 13%. In two syncopal patients, a sudden increase in pectoral oxygen saturation preceded cerebral oxygen desaturation and unconsciousness, suggesting a sudden loss of peripheral sympathetic tone. Simultaneous desaturation in both tissues in the other two patients appeared to be in response to a diminished cardiac output. The muscle and brain oxygen saturation ratio increased by 75% with apparent sympathetic dysfunction, but never changed by > 25% in the other patients, and varied by < 15% in the volunteers. These results suggest that during tilt table testing, simultaneous assessment of brain and skeletal muscle oxygenation may provide a simple, objective aid for the identification of contributory sympathetic dysfunction.

Role of the serotonergic system in the genesis of vasovagal syncope.

AIMS: The hypotensive reflex responsible for vasovagal syncope appears related to a reduction in sympathetic neural outflow. Several animal studies suggest that serotonin may play a role in the genesis of this reflex, through inhibition of sympathetic activity. However, the role of the serotonergic system is unknown in humans. The purpose of the study was to investigate the role of the serotonergic system in the genesis of vasovagal syncope by means of the level of platelet and plasma serotonin, as well as plasma catecholamines, during tilt-induced syncope. METHODS AND RESULTS: Fifteen patients (age 34 +/- 16 years) with vasovagal syncope underwent a head-up tilt test (HUT, 60 degrees , 45 min). If syncope did not develop, 300 microg nitroglycerin was administered sublingually and patients continued to be tilted for a further 20 min. Blood samples were obtained in the supine position, and then after 3, 10, 15, 30, 45, 48 and 65 min of HUT. If syncope developed, blood samples were obtained at the beginning of the prodrome, during syncope and after the recovery of consciousness. Platelet and plasma serotonin and plasma catecholamines were measured using high-pressure liquid chromatography with electrochemical detection. Ten patients developed syncope during the unmedicated HUT and four after nitroglycerin. In these patients plasma adrenaline significantly increased from the last programmed sample before the prodrome to its beginning and showed a further increase during loss of consciousness, whereas plasma noradrenaline did not increase, as an expression of inhibition of sympathetic neural outflow. In the patients experiencing syncope, both platelet and plasma serotonin showed no significant change after tilt-up, at the beginning of prodrome, during syncope and after recovery of consciousness. CONCLUSION: These results do not suggest that the serotonergic system plays a role in the pathophysiology of vasovagal syncope.

Pathophysiologic basis for vasodepressor syncope.

The current knowledge regarding the pathophysiologic basis of the vasodepressor response was reviewed. The balance of evidence indicates that the mechanoreceptor hypothesis seems unlikely to be the sole afferent alteration that leads to the vasodepressor response. Alternative afferent mechanisms should include neurohumoral mediated sympathoinhibition triggered by opioid mechanisms as well as impaired endothelial and NO responses to orthostatic stress in susceptible individuals. It is possible that impaired cardiovagal and sympathetic outflow control of arterial baroreceptors is enhanced by the aforementioned mechanisms. The role of central sympathoinhibition and vagal excitation triggered directly from pathways within the temporal lobe or triggered by alterations in regional cerebral blood flow should be considered as potential alternative mechanisms. Efferent autonomic outflow during vasodepressor syncope include sympathetic neural outflow withdrawal in addition to activation of parasympathetic outflow to the heart and abdominal viscera. Further human research is needed to understand the underlying mechanisms that result in the described neural and vascular responses.