Search

Neurally mediated syncope (NMS) arises from a neural reflex; however, its underlying cause remains unknown. Previous research has shown that variations in the Gi-α signal transduction rate led to changes in adenylate cyclase (AC) activity levels. Thus, we hypothesized that these fluctuations in AC activity could contribute to NMS. This study aimed to investigate the receptor genes associated with glutamate (Glu) repeat polymorphism sites Glu12 and Glu9 in the α2B-AR gene. A total of 50 patients with vasodepressor-type (VT)-NMS and 20 healthy volunteers were included in this study. We assessed AC activity levels and blood pressure responses during the head-up tilt (HUT) test and conducted a Glu repeat polymorphism analysis to explore its potential association with NMS. Our findings showed significantly higher AC activity in patients with the Glu12/12 homotype than healthy volunteers across all four HUT test points. Conversely, patients with the Glu9/12 heterotype exhibited a significant difference only 10 min after the test initiation, suggesting a pronounced activation effect of the β2-AR Gs-α subunit in these individuals. Both genotypes displayed the greatest blood pressure fluctuations under 70° tilt stress, with patients with Glu12/12 showing consistent cardiac load and higher values than those with Glu9/12 at two points. Notably, the frequency of NMS onset within 20 min during the tilt test varied, with one Glu12/12 patient and seven Glu9/12 patients experiencing syncope. Additionally, patients with the Glu9/12 heterotype were found to have a higher risk of syncope after prolonged standing compared to those with the Glu12/12 homotype. These results suggest that patients with the Glu12/12 homotype exhibit elevated AC activity levels, which may help increase blood pressure to prevent syncope. This study underscores that variations in AC activity among different gene types could influence the frequency of NMS onset during standing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Komiyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The vasovagal syncope (VVS) is the most common form of syncope. The mechanisms of VVS development are not entirely clear. It is known that there is a genetic predisposition to this disease, but the data on the roles of individual genes are quite contradictory. Recently, a genome-wide association study identified a locus at chromosome 2q32.1 associated with a united group of diseases, that is, syncope and collapse; among the single nucleotide polymorphisms (SNPs) of this locus, the most significant association was observed for rs12465214. In a homogeneous sample of patients diagnosed with VVS, we analyzed the association of rs12465214, rs12621296, rs17582219 and rs1344706 located on chromosome 2q32.1 with this form of syncope. In the enrolled set, only rs12621296 was associated with VVS by itself, whereas associations of other SNPs were observed only in biallelic combinations. An epistatic interaction between the components of the combination rs12621296*A + rs17582219*A was revealed. The possible involvement of individual genes on the 2q32.1 locus in the genetic architecture of the VVS is discussed.

Background and Objective: Head-up tilt test (HUTT) is clinically advantageous for diagnosing patients with vasovagal syncope (VVS). Nitroglycerin is mainly used as a stimulant during HUTT, and mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in the metabolism of nitroglycerin (NTG). ALDH2 Glu487Lys polymorphism (ALDH2 rs671) is the most common variant in the East Asian population. This study aimed to assess the effects of ALDH2 rs671 on VVS patients undergoing HUTT supplemented with sublingual NTG (HUTT-NTG).  METHODS: Patients with recurrent VVS (at least 2 times) who were admitted to the syncope center of our hospital were enrolled. All VVS patients have undergone HUTT. The polymorphism of Glu487Lys gene of ALDH2 was measured by the DNA Microarray Chip Method. The results of HUTT-NTG of VVS patients with different ALDH2 genotypes were compared and their hemodynamic characteristics were assessed., Results: A total of 199 VVS patients were enrolled, including 101 patients in the ALDH2*1/*1 group and 98 patients in the ALDH2*2 group. Among patients undergoing HUTT-NTG, 70.3% of patients in the ALDH2*1/*1 group and 68.4% of patients in the ALDH2*2 group were positive, and the difference between the two groups was not statistically significant (P = 0.77). The proportions of VASIS I, VASIS II, and VASIS III were 40.6%, 8.9%, and 20.8% in the ALDH2*1/*1 group, respectively, and the corresponding proportions in the ALDH2*2 group were 36.7%, 11.2%, and 20.4%, respectively. There was no statistically significant difference between the two groups (P = 0.91). The hemodynamic characteristics of different genotypes in VVS patients undergoing HUTT-NTG were compared, and no statistically significant difference was found. The median time of syncopal episode occurred after NTG administration in the ALDH2*1/*1 group was 6 min (interquartile range [IQR]: 5.0-9.0), and it was 6.0 min in the ALDH2*2 group (IQR: 4.25-8.0, P = 0.64)., Conclusion: ALDH2 Glu487Lys polymorphism did not affect the outcome of VVS patients undergoing HUTT-NTG, and no significant change in the hemodynamic characteristics of different genotypes was found., (© 2022. The Author(s).)

Vasovagal syncope (VVS) is the most common cause of sudden loss of consciousness. VVS results from cerebral hypoperfusion, due to abnormal autonomic control of blood circulation, leading to arterial hypotension. It is a complex disease, and its development is largely associated with genetic susceptibility. Since abnormal neurohumoral regulation plays an important role in VVS development, we analyzed the association of VVS with polymorphic variants of ADRA1A , ADRB1 , HTR1A , ADORA2A , COMT , and NOS3 genes, the products of which are involved in neurohumoral signaling, in patients with a confirmed VVS diagnosis (157 subjects) and individuals without a history of syncope (161 subjects). We were able to identify the associations between VVS and alleles/genotypes ADRA1A rs1048101, ADRB1 rs1801253, ADORA2A rs5751876, and COMT rs4680, as well as NOS3 rs2070744 in biallelic combination with COMT rs4680. Thus, we are the first to observe, within a single study, the role of the genes that encode α- and β-adrenergic receptors, catechol-O-methyltransferase, adenosine receptors and nitric oxide synthase in VVS development. These findings demonstrate that the genes involved in neurohumoral signaling pathways contribute to the formation of a genetic susceptibility to VVS.

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.