Europace Advance Access originally published online on April 26, 2007
Europace 2007 9(8):585-588; doi:10.1093/europace/eum059
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BASIC SCIENCE
The Arg389Gly ß1-adrenergic receptor gene polymorphism and susceptibility to faint during head-up tilt test
1 Department of Electrocardiology, Instituto Nacional de Cardiología ‘Ignacio Chávez’, Mexico City, Mexico; 2 Department of Physiology, Instituto Nacional de Cardiología ‘Ignacio Chávez’, Juan Badiano 1, Col. Sección XVI, Tlalpan 14080, México, D.F., Mexico; 3 Cardiovascular Diseases Genomic and Proteomic Study Group, Instituto Nacional de Cardiología ‘Ignacio Chávez’, Mexico City, Mexico
Manuscript submitted 9 August 2006. Accepted after revision 8 March 2007.
* Corresponding author. Tel: 5255 5573 2911/ext. 1278; fax: 5255 5573 0926. E-mail address: gvargas63{at}yahoo.com
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Abstract |
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Aims To investigate the association of the Gly389 allele with positive head-up tilt test (HUT) in a Mexican Mestizo population.
Methods and results HUT results were compared between carriers (one or two copies of the Gly389 allele) and non-carriers (Arg389Arg genotype) of the Gly389 allele of the ß1AR gene in 50 patients with unexplained syncope. Thirty-three patients (66%) had a positive HUT. Patients with a positive HUT had a higher Gly389 allele frequency compared with those with a negative test (30.3 vs. 3%; OR 13; pC = 0.012). Moreover, when comparing positive HUT in passive drug-free phase, positive HUT in pharmacological (nitrate) phase, and negative (both phases), a decreasing gradient in the frequencies of the Gly389 allele was found among the three groups: 45.4, 22.7, and 3%, respectively.
Conclusion An association of positive tilt table testing to a single nucleotide polymorphism with a Gly to Arg switch at position 389 of the ß1AR was found. This polymorphism may contribute to susceptibility to faint during orthostatic challenge.
Key Words: Autonomic nervous system, Adrenergic receptors, Vasovagal syncope, Genetics
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Introduction |
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Vasovagal syncope (VVS) is characterized by transient episodes of loss of consciousness usually preceded by premonitory signs and symptoms.1
The autonomic nervous system plays a fundamental role in the pathophysiology of VVS.2 Dysregulation of the autonomic nervous system may be the result of functional alterations in adrenergic receptors produced by functional gene polymorphisms. Subjects with the Glycine allele in position 389 (Gly389) of the ß1-adrenergic receptor (ß1AR) have been shown to have a significantly lower contractile responsiveness to catecholamines.3 The purpose of this study was to explore the presence of polymorphisms of the ß1AR in this position, in patients submitted to head-up tilt test (HUT). |
Methods |
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Fifty consecutive patients from a Mexican Mestizo population, with more than one episode of unexplained syncope and who underwent HUT, were studied. Patients with structural heart disease, sick sinus syndrome, intraventricular conduction disturbance, orthostatic hypotension, atrial fibrillation, permanent implanted pacemakers, or other causes of syncope were not enrolled. None was under ß-blocker treatment.
HUT: The test was performed in a quiet room and after overnight fasting after 5 min at rest in the supine position. Subjects were tilted to 70° head-up, using a motorized tilt-table with a foot-board support. The test was considered to be positive when syncope occurred accompanied by systemic hypotension (systolic BP <80 mmHg or >30% reduction from baseline) and/or bradycardia (heart rate <50 bpm or >20% reduction in heart rate from baseline). All patients were rapidly returned to the supine position once systemic hypotension was evident.
During the test, ECG leads I, II, and III were continuously monitored; brachial blood pressure was assessed during the test by an sphygmomanometric method. When passive HUT was negative after 30 min, the patient was returned to the supine position and 5 mg of sublingual isosorbide was administered. The HUT was repeated for 12 min.
DNA extraction: Genomic DNA was isolated from peripheral blood by a rapid non-enzymatic method.4
Polymorphisms detection: Polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism method with primers previously described.5 The Arg389Gly polymorphic site was amplified using the 5'-CGCTCTGCTGGCTGCCCT- TCTTCC-3' (sense) and 5'-TGGGCTTCGAGTTCACCTGCTATC-3' (antisense) primers. This was followed by a restriction enzyme digestion (Bcg I). Cleavage of amplified fragments was detected by electrophoresis in 12% acrilamide gel and visualized by silver staining.
Statistical analysis
Allele frequencies of the ß1AR gene polymorphism were obtained by direct counting. Hardy–Weinberg equilibrium was evaluated by 
2 test. Allelic frequencies were compared with the different HUT results by 2 test that combined the 2 x 2 contingency tables, and ANOVA, using SPSS 12, and were considered significantly different if the P-values were <0.05. The P-values were corrected according to Bonferroni. Relative risk with 95% confidence interval (95% CI) were estimated as the odds ratio (OR) by Woolf method.6
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Results |
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Thirty-three patients had a positive HUT, 11 in the passive phase (Group A), 22 in the isosorbide phase (Group B), and 17 were negative to both (Group C). Baseline characteristics (gender, age, blood pressure, heart rate) were similar in all three groups as shown in Table 1.
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Analysis of the total population showed an allele frequency for Arg389 of 79% and for Gly389 of 21% (Table 2). Allele frequencies were in Hardy–Weinberg equilibrium.
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The Gly389 allele frequency in positive HUT patients was higher than in the negative group (30.3 vs. 3%; OR 13; pC = 0.012; Table 3). A gradient of allelic frequencies in polymorphism Arg389Gly was found when patients were analysed according to the HUT responses (Figure 1). The Gly389 allele frequency in subjects of groups A, B, and C was 45, 22, and 3%, respectively (pC < 0.0001).
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Discussion |
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Distribution of ß1AR polymorphisms in Mexican healthy individuals has been previously reported by our group: 85 Arg389, 15 Gly389.7
Analysis of the total population in this study showed similar allele frequencies (Arg 79%, Gly 21%) to these healthy subjects and to those reported by other authors, also in healthy subjects (Table 2).3,8,9 When patients were analysed according to HUT result, those with a positive HUT had significantly increased frequencies of Gly389 allele (30.3 vs. 3%) compared with those with a negative HUT. Supporting this finding, a decreasing gradient in the Gly389 allele frequencies was found between patients with passive positive HUT, isosorbide-induced positive HUT, and negative HUT: 45.4, 22.7, and 3%, respectively.
The ß1AR, a member of the adrenergic family of G-protein-coupled receptors, is the predominant subtype in the heart (80%), and is located on chromosome 10q24–26. It was cloned in 1987.10 Signalling through this receptor subtype is important for cardiac chronotropism, inotropism, and dromotropism.11 Evidence indicates that the tendency to faint due to VVS is multifactorial, with genetic, psychological, and environmental factors involved.12–14
Specific alleles of two polymorphisms (Arg389Gly, Ser49Gly) have a high prevalence in patients with cardiovascular problems.15–18 Experimental studies had demonstrated a functional role of polymorphism Arg389Gly. Mason et al.8 reported that this polymorphism produces functional effects by altering the Gs-protein coupling domain of the human ß1AR, with a gain-of-function for the Arg389 subtype. Another study, using right atrial appendage tissue (obtained during cardiac surgery) revealed a greater inotropic response to noradrenaline in Arg389Arg compared with Gly389Gly patients.19 Although some authors state that the Arg389Gly polymorphism has only minor relevance in vivo, in genotype-discordant sibling pair analysis, Bengtsson et al.20 observed that siblings homozygous for the Arg389 allele had significantly higher heart rates than siblings carrying the Gly389 allele. Bruck et al.21 showed that dobutamine infusion caused larger HR and contractility increases in Arg389 vs. Gly389 subjects. La Rosée et al.3 showed that homozygous subjects for the Arg389 ß1AR had a significantly higher increase in fractional shortening upon cumulative doses of dobutamine when compared with subjects carrying one or two copies of the Gly389 allele. Winker et al.22 found no correlation between this polymorphism among controls and patients with postural orthostatic tachycardia syndrome. However, this syndrome is a subtype of orthostatic intolerance with a different pathophysiology than VVS.23
If the inotropic response to cathecolamines is diminished in subjects with the Gly389 allele as has been shown in other studies, it could be suggested that these subjects might be susceptible to develop a positive HUT through decreased cardiac inotropic response to orthostatic challenge. Although a small number of patients were enrolled in the present study, the data obtained are highly significant. Further studies are underway to correlate haemodynamic parameters with polymorphic variations in the ß1AR.
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Conclusion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
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The tendency to faint due to VVS is multifactorial, with genetic, psychological, and environmental factors involved. In this study, an association of positive HUT to a single nucleotide polymorphism at position 389 of the ß1AR gene was found. This polymorphism could contribute to susceptibility to faint during orthostatic challenge.
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Acknowledgements |
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This work was supported in part by grants from the Consejo Nacional de Ciencia y Tecnología, México, DF, México. The authors are grateful to Elizabeth Salas, RN, JM Rodríguez-Pérez, BS, BettyLou Chinn, RN and N Pérez-Vielma, BS for their contributions to the present work.
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Footnotes |
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The two authors contributed equally and the order of authorship is arbitrary. 
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References |
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