|Year : 2016 | Volume
| Issue : 3 | Page : 13-19
Amiodarone treatment investigation on the correlation between the drug sensitivity for paroxysmal atrial fibrillation and gene polymorphism
Shuxin Hou, Yingmin Lu, Damin Huang, Zhaoxia Wang, Xiaohan Luo, Jinchun Zhang, Jian Ji, Lei Song, Zhihua Li, Caiwen Wei, Zengyan Zhao, Weiping Xu
Department of Cardiology, Shanghai Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China
|Date of Web Publication||26-Dec-2018|
Prof. Weiping Xu
Department of Cardiology, Affiliated Xinhua Hospital (Chongming Branch), Shanghai Jiaotong University, School of Medicine, 25 South Gate Road, Chengqiao Town Chongming County, Shanghai 202150
Source of Support: None, Conflict of Interest: None
Objective: To investigate the correlation between the sensitivity to amiodarone therapy and the polymorphism of KCNN3 gene rs13376333 site and ZFHX3 gene rs7193343 site in patients with paroxysmal atrial fibrillation (AF). Materials and Methods: A total of 100 patients comprised 57 men and 43 women with paroxysmal AF hospitalized in Xinhua Hospital were selected between November 1, 2014, and April 30, 2016. Their clinical data and peripheral venous blood samples were collected for case–control study. Patients with recovered to sinus rhythm that was maintained for 6 months in response to amiodarone treatment were included in the observational group. Patients whose rhythm could not be converted to sinus rhythm after amiodarone treatment or who had recurrence within 6 months were included in the control group. DNA of the white blood cells collected from the peripheral venous blood was extracted for each group. The polymerase chain reaction-restriction fragment length polymorphism method and gene sequencing were used to detect the genotype of KCNN3 gene rs13376333 site and ZFHX3 gene rs7193343 site in all the patients. The polymorphism in KCNN3 gene rs13376333 site and ZFHX3 gene rs7193343 was analyzed between the observational and control groups. Results: Three genotypes for KCNN3 gene rs13376333 in the observational and control groups were identified: TT, TC, and CC. The genotype frequency was 26% versus 20% for TT, 40% versus 36% for TC, and 34% versus 44% for CC and 46% versus 38% for T allele and 54% versus 62% for C allele, respectively. However, differences were not statistically significant (P > 0.05). More patients in the observational group carried T allele than that in the control group. Logistic regression indicated a 1.21-fold increase in sensitivity to amiodarone by T allele for the treatment of paroxysmal AF (odds ratio [OR] =1.21, P > 0.05). However, this result was not statistically significant. There were three genotypes for ZFHX3 gene rs7193343 site in both groups: 28% versus 42% for TT, 42% versus 42% for TC and 30% versus 16% for CC and 49% versus 63% for T allele and 51% versus 37% for C allele, respectively. More patients in the observational group carried C allele than that in the control group. Logistic regression indicated a 1.32-fold increase in the sensitivity to amiodarone by the C allele for the treatment of paroxysmal AF (OR = 1.32, P < 0.05). Conclusion: Gene polymorphism was present at KCNN3 gene rs13376333 site and ZFHX3 gene rs7193343 in the observational and control groups, respectively. However, there was no statistical difference in the genotype and allele frequency of KCNN3 gene rs13376333 between the two groups. The effect on the sensitivity to amiodarone in the treatment of paroxysmal AF could not yet be determined. The C allele at ZFHX3 gene rs7193343 site significantly increased the sensitivity to amiodarone for paroxysmal AF.
Keywords: Amiodarone, gene polymorphism, paroxysmal atrial fibrillation
|How to cite this article:|
Hou S, Lu Y, Huang D, Wang Z, Luo X, Zhang J, Ji J, Song L, Li Z, Wei C, Zhao Z, Xu W. Amiodarone treatment investigation on the correlation between the drug sensitivity for paroxysmal atrial fibrillation and gene polymorphism. Cardiol Plus 2016;1:13-9
|How to cite this URL:|
Hou S, Lu Y, Huang D, Wang Z, Luo X, Zhang J, Ji J, Song L, Li Z, Wei C, Zhao Z, Xu W. Amiodarone treatment investigation on the correlation between the drug sensitivity for paroxysmal atrial fibrillation and gene polymorphism. Cardiol Plus [serial online] 2016 [cited 2021 Mar 3];1:13-9. Available from: https://www.cardiologyplus.org/text.asp?2016/1/3/13/248353
| Introduction|| |
Atrial fibrillation (AF) is the most serious atrial electrical rhythm disorder and the most common arrhythmia in clinical practice, with an overall prevalence of 0.77% in Chinese adults and up to 2.4% in the developed countries, including Europe and the United States., The risk for AF increases with age. With advances in the diagnostic and therapeutic technologies for cardiovascular diseases combined with the increasing aged population, the prevalence of AF rises annually and has become a major epidemic disease in the new century.,
AF has a high disability and mortality rate and the current therapeutic strategies to treat it are not ideal., Drug therapy continues to be the main approach for this indication; however, the recurrence rates are high. Molecular biological techniques have identified polymorphisms in genes encoding a variety of ion channels, including potassium, sodium, and calcium channels that are associated with the onset of AF.,,,,,, A meta-analysis of genome-wide association studies showed that a polymorphism of the calcium-activated potassium channel KCNN3 gene at the rs13376333 site significantly correlated with isolated AFs. Because the rs7193343 site of the zinc finger homebox3 (ZFHX3) gene is adjacent to KCNN3 gene rs13376333, the polymorphism of the ZFHX3 gene rs7193343 could also correlate with AF.,
Amiodarone is a Class III antiarrhythmic agent and is the most widely prescribed drug for rhythm control therapy to manage AFs. It blocks ion channels including potassium, sodium, and calcium channels and can inhibit β- and α-receptors. Its multiple activities at different potassium channels play a critical role in controlling AF by prolonging action potential duration and the effective refractory period.
Recent studies indicate that the drug sensitivity can correlate with polymorphisms in some genes; for example, the VKORC1-1639A/G polymorphism correlates with the sensitivity to warfarin anticoagulation therapy in patients with AF., It was found that the insertion/deletion (I/D) polymorphism of ACE gene can predict the failure rate of drug therapy for isolated AF., Furthermore, the DD/ID genotype significantly relates with the failure of drug therapy for isolated AF., Based on studies on the mechanism of actions of amiodarone on potassium channels and the correlation between the drug sensitivity and gene polymorphism, it is presumed that the polymorphism of potassium channel-related genes (KCNN3 gene rs13376333 and ZFHX3 gene rs7193343) could correlate with the sensitivity to amiodarone; however, no reports have been published. Therefore, this study investigated the polymorphism of the calcium-activated potassium channel KCNN3 gene rs13376333 and ZFHX3 gene rs7193343 and the sensitivity to amiodarone in patients with AF and explored the correlation of the polymorphism of rs13376333 and rs7193343 with the sensitivity to amiodarone in the treatment of AF. This study demonstrates that the genetic basis for the onset of AF and drug sensitivity can be used to guide the selection of drugs for treatment of AF.
| Materials and Methods|| |
Patients hospitalized between November 1, 2014, and April 30, 2016, in the Chongming Branch of XinHua Hospital affiliated with Shanghai Jiaotong University School of Medicine were selected for this study. All the patients were aged between 40 and 75 years and were previously diagnosed with paroxysmal AF determined by electrocardiogram (ECG) and dynamic ECG according to the diagnostic criteria in the 2014AHA/ACC/HRS guidelines on the management of AF. Patients with secondary hypertension, rheumatic heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, hyperthyroidism, electrolyte disorder, viral myocarditis, malignancies, serious cardiac failure (ejection fraction <40%), renal and hepatic insufficiency, or critical illness were excluded. A total of 100 patients comprised 57 men and 43 women were enrolled. This study was approved by the ethics committee in our hospital, and informed consent was received from the patients.
Basic information such as name, gender, age, ethnicity, address, and contact number of all eligible patients was recorded. History of smoking, alcohol consumption, and concomitant diseases and family history were collected. ECGs (Nihon KohdenECG1350 P), dynamic ECGs, blood pressure measurements, transthoracic echocardiography (PHLIPSiE33), thyroid function tests, electrolyte analyses, and renal and hepatic function tests (BECKMAN AU580) were also performed routinely.
Intervention and efficacy evaluation
amiodarone was first administered at 1 mg/min for 5 h, followed by 0.5 mg/min for 48–72 h. At the same time, the patients received 0.2 g tid po amiodarone for 2 week, which was reduced to 0.2 g bid po the following week, and 0.2 g qd po the subsequent week. ECG was followed up every 2 weeks in the outpatient department after discharge. The dynamic ECG was followed up every 4 weeks for ½ year. The patients with recurrent paroxysmal or persistent AF determined by ECG or dynamic ECG within 6 months were considered to have low sensitivity to amiodarone and were included in the control group, whereas those who were successfully converted and maintained sinus rhythm in ECG or dynamic ECG within 6 months were considered highly sensitive to amiodarone and were included in the observational group. There were 50 patients in each group with 100 total patients.
Each morning, 6 ml of fasting venous blood was collected in EDTA anticoagulation tubes for all patients. White blood cells were separated from serum by immediate centrifugation (4°C, 3000 g, and 15 min). The white blood cells were collected and stored at −80°C for central testing. A centrifugal column type DNA extraction kit (TiangenBiotech [Beijing] Co., Ltd.) was used to extract the genomic DNA from each sample, which was stored at −20°C for testing.,,,,,
Detection of KCNN3 gene rs13376333 and ZFHX3 gene rs7193343 polymorphism using polymerase chain reaction-restriction fragment length polymorphism method
Polymerase chain reaction (PCR) was used to amplify the fragment containing the target site. PCR amplification was performed using a 50 μl reaction system with 10 pmol/L of both upstream and downstream primers, 4 μl of genomic DNA, 5 μl of 10Xbuffer, 25 mM MgCl2, 2.0 mM dNTPs, and 1 μl Taq DNA polymerase. Diethylpyrocarbonate (DEPC) treated water was added to reach a final volume of 50 μl and the reaction tube was placed in a PCR thermal cycler (Shanghai Maisheng Technology Co., Ltd., model CFX96). The PCR reaction was performed according to the following protocol: Pre-denaturation for 5 min at 95°C →denaturation for 1 min at 94°C →renaturation for 1 min at 56°C →extension for 1 min at 72°C (from denaturation for 1 min at 94°C to this process for 40 cycles)→extension for 8 min at 72°C →placement at 4°C for storage. The primers designed were synthesized by Biotech Engineering Co., Ltd (Shanghai) [Table 1] and the product was purified using a PCR purification kit.
The PCR amplification product of KCNN3 gene rs13376333 and ZFHX3 gene rs7193343 was digested by the NdeI restriction enzyme. The enzyme digestion reaction system (20 μl) was composed of 2 μl of 10X buffer, 1 μl of NdeI restriction enzyme, 12 μl of PCR product, and 5 μl of sterile double-distilled water and was incubated for 12 h in a water bath at 37°C. Low melting point agarose gel electrophoresis was performed for the enzyme digestion product (100 V for 60 min). The result of enzyme digestion was photo analyzed, images were saved using the Bio-Best14OE gel imaging system, and the type of KCNN3 gene rs13376333 and ZFHX3 gene rs7193343 was identified.
Detection of the polymorphism of KCNN3 gene rs13376333 and ZFHX3 gene rs7193343 using gene sequencing
Ten specimens were randomly selected from the two groups, respectively. Their previous PCR products were purified and recovered using a PCR product purification and recovery kit (Biotech SK1141); then, direct gene sequencing was performed in a 3730 sequence analyzer (US ABI).
IBM SPSS15.0 software was used for statistical analyses. Normal distribution tests were performed for all measured data that met normal distribution represented as X ± S and were tested using independent-sample t-test. Data with skewed distributions were represented as median (P25–P75) and tested using the Mann–Whitney test. The Chi-square test was used for intergroup comparison of enumeration data. All the above statistical tests were two-sided probability test. The difference was considered statistically significant at P < 0.05.
| Results|| |
Basic information of patients in observational group and control group
A total of 100 patients comprised 57 men and 43 women with paroxysmal AFs hospitalized at the Chongming Branch of XinHua Hospital between November 1, 2014. and April 30, 2016. were enrolled in this study. Patients poorly sensitive to amiodarone identified by recurrence of the disease within 6 months were included in the control group, whereas patients highly sensitive to amiodarone with converted and maintained sinus rhythm within 6 months were included in the observational group. There were 50 patients in each group with no significant differences in gender, age, concomitant disease, blood pressure, echocardiography, and serum chemistry between the two groups (P ≥ 0.05) [Table 2].
|Table 2: Comparison of the clinical data between observational group and control group|
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Peripheral blood DNA extraction
Genomic DNA was extracted from white blood cells. The DNA concentration was measured to be 26–52 ng/μl and the A260/A280 absorbance ranged from 1.8 to 2.0, indicating DNA purity in accordance with the experimental requirement. A 2% agarose gel electrophoresis was performed for 60 min at voltage of 100 V and resulted in clear bands of genomic DNA in the electrophoretogram with no band interference [Figure 1].
Genotype and allele frequency
The agarose gel electrophoresis of PCR-RLFP (Restriction Fragment Length Polymorphism) reaction product showed the presence of three genotypes of KCNN3 gene rs13376333: TT, TC, and CC [P > 0.05, [Table 3]. The genotype distribution frequency was in line with the genetic equilibrium law, indicating the sample selected could represent the population profile. The genotype and allele distribution were different between the observational and control groups: 26% versus 20% for TT, 40% versus 36% for TC, and 34% versus 44% for CC and 46% versus 38% for T allele and 54% versus 62% for C allele, respectively; however, the difference was not statistically significant [P > 0.05, [Table 4]. More patients in the observational group carried the T allele than that in control group. Logistic regression showed a 1.21-fold increase to the sensitivity to amiodarone in treatment of paroxysmal AF by the T allele (odds ration [OR] = 1.21, P > 0.05); however, this difference was not significant.
|Table 3: Hardy-Weinberg equilibrium test for allele frequency of KCNN3 gene rs13376333 between observational group and control group|
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|Table 4: Distribution of allele and genotype frequency of KCNN3 gene rs13376333 between observational group and control group|
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The agarose gel electrophoresis showed the presence of three genotypes of ZFHX3 gene rs7193343: TT, TC, and CC [P > 0.05, [Table 5]. The genotype distribution frequency was in line with genetic equilibrium law, indicating the sample selected could represent the population profile. The genotype and allele distribution were all significantly different between the observational group and control group (P < 0.05): 28% versus 42% for TT, 42% versus 42% for TC, 30% versus 16% for CC and 49% versus 63% for T allele and 51% versus 37% for C allele, respectively [Table 6]. More patients in the observational group carried T allele. The logistic regression showed a 1.32-fold increase in sensitivity to amiodarone in the treatment of paroxysmal AF by the C allele (OR = 1.32, P < 0.05).
|Table 5: Hardy-Weinberg equilibrium test for allele frequency of ZFHX3 gene rs7193343 between observational group and control group|
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|Table 6: Distribution of allele and genotype frequency of ZFHX3 gene rs7193343 between observational group and control group|
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| Discussion|| |
Amiodarone is a Class III antiarrhythmic agent that mainly blocks potassium channels, prolongs the duration and the refractory period of myocardial action potentials, and decreases conduction velocity and membrane reactivity. It is used to control ventricular rate and rhythm in AF and is the most effective drug for the maintenance of sinus rhythm in patients with AF and atrial flutter. However, clinical studies report that 30%–50% patients are still not sensitive to amiodarone treatment and are unable to maintain long-term sinus rhythm.,
It was previously reported in clinical trials that 63.29%–67.57% patients could maintain sinus rhythm within 6 months after conversion of AF with amiodarone and this proportion decreased with the time; however, the comparability of the results was poor due to the differences in the type of AF, age, concomitant medications, and cardiac diseases selected in each clinical trial., In the present study, 50% of the patients had successful cardioversion and maintained sinus rhythm within 6 months. Considering the longevity of the township for Chongming County, there was a relationship with the slightly higher average age and higher proportion of patients with concomitant hypertension and coronary heart disease. Moreover, the patients who could not be converted to sinus rhythm with amiodarone were included in the nonsensitive group in this trial. In addition to those who could not maintain sinus rhythm within 6 months, more patients were not sensitive to amiodarone as compared with those in other studies. In addition, the factor of genetic heterogeneity could not be excluded. It was recently found that single-nucleotide polymorphisms in genes encoding ion channels in the myocardial cells affected the action potentials in atrial myocytes and can lead to atrial electrical reconstruction, thereby increasing the occurrence of AF. Studies on the correlation between the single-nucleotide polymorphisms in the genes encoding potassium channels and the occurrence of AFs were further conducted. KCNN3 is a gene encoding small conductance calcium-activated potassium channel (SK3), and it was discovered that mutations in this gene increase susceptibility to AFs. SK3 is a tetramer comprised α subunit, calmodulin (CaM), protein kinase CKZ, and protein phosphatase ZA, where α subunit is the core and CaM is the regulatory fraction. The combination of Ca2+ with CaM can induce a change in the conformation of SK channels causing the channel to open., Patch-clamp electrophysiological experiments conducted by Giles in 1988 demonstrated that calcium-activated potassium channels (SK channels) were present in rabbit myocardial cells, and the expression of this channel in atrial myocytes was higher than that in ventricular myocytes. The current intensity of calcium-activated channels varied among cells of the same site, i.e., the distribution of SK channels was atrial selective. In 2010, the study conducted by Ellinor et al. showed that polymorphic change was present at KCNN3 gene rsl3376333 in patients with isolated AF and the risk for isolated AF was increased by 52%. Currently, there are few reports on investigations on gene polymorphism and sensitivity to antiarrhythmic agents. The present study showed T/C polymorphic change at KCNN3 gene rsl3376333 in the observational and control groups; the sensitivity to amiodarone in the treatment of paroxysmal AF was increased 1.21-fold by the T allele (OR = 1.21, P > 0.05); however, the differences were not statistically significant. The effect of the gene polymorphism at KCNN3 gene rsl3376333 on the sensitivity to amiodarone in patients with paroxysmal AF could not yet be determined. Therefore, the sample size should be expanded for further investigation and exploration.
The ZFHX3 gene encodes a transcription factor with ring-type zinc finger motifs and plays an important role in the pathophysiology of reconstruction and inflammatory change in myocardial cells by regulating the signal transducer and activator of transcription 3-mediated signal transduction pathway and consequently enhancing the transcription and expression of CRP. It plays a role in the electrical activity of myocardial cells by regulating intracellular calcium concentrations., Wang et al. showed that that the T allele at ZFHX3-rs7193343 increased the risk for AF 1.268-fold (P < 0.05, OR = 1.268, 95% confidence interval 1.012–1.590). The polymorphism at ZFHX3 gene rs7193343 affected intracellular calcium homeostasis, and the functional status of SK3 was modulated by the calcium concentration in myocardial cells. Gene polymorphism was found in both the observational group and control group in this study, and the difference was statistically significant (P < 0.05); the rate of the CC genotype was increased in the observational group and the sensitivity to amiodarone for the treatment of paroxysmal AF was increased by 1.32-fold by the C allele (OR = 1.32, P < 0.05). In summary, the ZFHX3 gene rs7193343 T allele increased the risk for AF whereas the C allele increased the sensitivity to amiodarone in patients with paroxysmal AF.
This study showed investigations of gene polymorphism could bring a new hope for the control of rhythm in AF. However, given the wide array of ion channels involved in AFs and complicated gene polymorphisms, the correlation between drug sensitivity and gene polymorphism requires much further exploration.
Financial support and sponsorship
Project funded by the Science and Technology Committee of Chongming county (Number: CQYL2014-08).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]