Gene polymorphism as a cause of hemorrhagic complications in patients with non-valvular atrial fibrillation treated with oral vitamin K-independent anticoagulants.

Atrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that have been proven to prevent stroke in patients with non-valvular AF. This review summarizes the pharmacokinetics, pharmacodynamics, and drug interactions of DOACs, as well as new data from pharmacogenetic studies of these drugs. This review is aimed at analyzing the scientific literature on the gene polymorphisms involved in the metabolism of DOACs. We searched PubMed, Cochrane, Google Scholar, and CyberLeninka (Russian version) databases with keywords: 'dabigatran', 'apixaban', 'rivaroxaban', 'edoxaban', 'gene polymorphism', 'pharmacogenetics', 'ABCB1', 'CES1', 'SULT1A', 'ABCG2', and 'CYP3A4'. The articles referred for this review include (1) full-text articles; (2) study design with meta-analysis, an observational study in patients taking DOAC; and (3) data on the single-nucleotide polymorphisms and kinetic parameters of DOACs (plasma concentration), or a particular clinical outcome, published in English and Russian languages during the last 10 years. The ages of the patients ranged from 18 to 75 years. Out of 114 reviewed works, 24 were found eligible. As per the available pharmacogenomic data, polymorphisms affecting DOACs are different. This may aid in developing individual approaches to optimize DOAC pharmacotherapy to reduce the risk of hemorrhagic complications. However, large-scale population studies are required to determine the dosage of the new oral anticoagulants based on genotyping. Information on the genetic effects is limited owing to the lack of large-scale studies. Uncovering the mechanisms of the genetic basis of sensitivity to DOACs helps in developing personalized therapy based on patient-specific genetic variants and improves the efficacy and safety of DOACs in the general population.

Gene polymorphism as a cause of hemorrhagic complications in patients with non-valvular atrial fibrillation treated with oral vitamin K-independent anticoagulantsAtrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that have been proven to prevent stroke in patients with non-valvular AF. This review summarizes the pharmacokinetics, pharmacodynamics, and drug interactions of DOACs, as well as new data from pharmacogenetic studies of these drugs.

Routine use of a 3D mapping system in the ablation of supraventricular arrhythmias with as low as reasonably achievable X-ray exposure (AALARA): protocol for a prospective, observational, multicentre, multinational, open-label registry study.

INTRODUCTION: The reduction of fluoroscopic exposure during catheter ablation of supraventricular arrhythmias is widely adopted by experienced electrophysiology physicians with a relatively short learning curve and is becoming standard of care in many parts of the world. While observational studies in the USA and some parts of Western Europe have evaluated the minimal fluoroscopic approach, there are scarce real-world data for this technique and generalisability of outcome in other economic regions. METHODS AND ANALYSIS: The arrhythmias with as low as reasonably achievable X-ray exposure study is a prospective, observational, multicentre and multinational open-label registry study. Up to 700 patients undergoing catheter ablation for right-sided supraventricular arrhythmias (according to national guidelines) will be enrolled for the routine use of the EnSite Precision 3D mapping system. Participating sites are distributed in 13 countries from Central Eastern Europe, North and South Africa, the Middle East and the CIS (Commonwealth of Independent States), with different levels of expertise using minimal fluoroscopic exposure techniques. After electrophysiological procedure, patients will be followed up for 6 months either in-clinic or via telephone interview. Patients will be asked to complete a study questionnaire at enrolment and 6 months after the invasive procedure to assess quality of life changes secondary to the procedure. The study's primary objective is to describe ionising radiation exposure during catheter ablation when the EnSite Precision 3D mapping system is used in supraventricular tachycardia ablation. The study's secondary objective is to assess the safety and efficacy of this method. Furthermore, fluoroscopy timing, total procedure time, success rate and complications will be reported. ETHICS AND DISSEMINATION: The study was approved by the ethics committee at Mohammed Bin Khalifa Specialist Cardiac Centre (BDF/R&REC/2020-504) and the medical ethics committees of all participating sites. Participants will be required to provide informed consent before enrolment in the study. The study results will be published and presented at conferences. TRIAL REGISTRATION NUMBER: NCT04716270.

Left lateral decubitus computed tomography before catheter ablation in patients with atrial fibrillation.

Aim    The study aimed to determine the efficacy of cardiac computed tomography angiography (CCTA) for diagnosing left atrial appendage (LAA) thrombus before catheter ablation with the patient in the left lateral decubitus position and, also, to evaluate the risk factors for thrombus formation.Material and methods    This retrospective, cohort study included 101 patients with atrial fibrillation. All patients underwent transthoracic echocardiography (TTE) and left lateral decubitus CCTA. Transesophageal echocardiography (TEE) was performed to confirm or exclude LAA thrombus. Patients with allergic reactions to iodinated contrast media, increased serum creatinine, hyperthyroidism, pregnancy, and age<18 years were excluded. The CHA2­DS2­VASc and HAS-BLED scores were calculated for each patient.Results    All LAA thrombi detected on CCTA were confirmed by TEE. Higher CHA2­DS2­VASc, HAS-BLED scores, enlarged LA, and the anteroposterior dimension of the left atrium were significantly associated with the presence of LAA thrombus. A LAA cauliflower shape was a predictor of thrombus. An increase of LAA volume by 1 ml increased the chances of LAA thrombus and cerebral ischemic infarct by 2 %. The growth of the LAA anteroposterior diameter by 1 cm increased the risk of LAA thrombus by 190 % and of cerebral infarct by 78 %. An increase in the CHA2DS2­VASc score by 1 point increased the risk of thromboembolism and cerebral infarction by 12 %.Conclusions    CCTA performed in the left lateral decubitus position of the patient is an optimal screening tool to detect or exclude LAA thrombus before catheter ablation because of atrial fibrillation. CCTA has predictive value for risk of thrombosis formation in LAA.

The Distribution of the Genotypes of ABCB1 and CES1 Polymorphisms in Kazakhstani Patients with Atrial Fibrillation Treated with DOAC.

Nowadays, direct oral anticoagulants (DOACs) are the first-line anticoagulant strategy in patients with non-valvular atrial fibrillation (NVAF). We aimed to identify the influence of polymorphisms of the genes encoding P-glycoprotein (ABCB1) and carboxylesterase 1 (CES1) on the variability of plasma concentrations of DOACs in Kazakhstani patients with NVAF. We analyzed polymorphisms rs4148738, rs1045642, rs2032582 and rs1128503 in ABCB1 and rs8192935, rs2244613 and rs71647871 CES1 genes and measured the plasma concentrations of dabigatran/apixaban and biochemical parameters in 150 Kazakhstani NVAF patients. Polymorphism rs8192935 in the CES1 gene (p = 0.04), BMI (p = 0.01) and APTT level (p = 0.01) were statistically significant independent factors of trough plasma concentration of dabigatran. In contrast, polymorphisms rs4148738, rs1045642, rs2032582 and rs1128503 in ABCB1 and rs8192935, rs2244613 and rs71647871 CES1 genes did not show significant influence on plasma concentrations of dabigatran/apixaban drugs (p > 0.05). Patients with GG genotype (138.8 ± 100.1 ng/mL) had higher peak plasma concentration of dabigatran than with AA genotype (100.9 ± 59.6 ng/mL) and AG genotype (98.7 ± 72.3 ng/mL) (Kruskal-Wallis test, p = 0.25). Thus, CES1 rs8192935 is significantly associated with plasma concentrations of dabigatran in Kazakhstani NVAF patients (p < 0.05). The level of the plasma concentration shows that biotransformation of the dabigatran processed faster in individual carriers of GG genotype rs8192935 in the CES1 gene than with AA genotype.

Performance of the ablation index during pulmonary vein isolation: periprocedural data from a multicenter registry.

PURPOSE: Our study aimed to assess the achievement of target ablation index (AI) values and their impact on first-pass pulmonary vein isolation (FPI) as well as to identify FPI predictors. METHODS: Atrial fibrillation (AF) ablation was performed according to the local practice, and target AIs were evaluated. The actual AI was calculated as the median value of all ablation points for the anterior and posterior left atrial (LA) walls. RESULTS: A total of 450 patients from nine centers were enrolled. Patients with first-time ablation (n = 408) were divided into the FPI and non-FPI groups. In the FPI group, a higher median target AI was reported for both the anterior and posterior LA walls than those in the non-FPI group. A higher actual AI was observed for the anterior LA wall in the FPI group. The actual AI was equal to or higher than the target AI for the posterior, anterior, and both LA walls in 54%, 47%, and 35% (n = 158) cases, respectively. Parameters such as hypertension, stroke, ablation power, actual AI value on the anterior wall, target AI values on both LA walls, AI achievement on the posterior wall, carina ablation, and operator experience were all associated with FPI in a univariate logistic regression model; only carina ablation was an independent predictor of FPI. CONCLUSIONS: According to our multicenter study, FPI and a target AI were not achieved in a significant proportion of AF ablation procedures. Higher actual and target AI values were associated with FPI, but only carina ablation can independently predict FPI.

Epidemiology of stroke and transient ischemic attacks in the population of the territories adjacent to the former Semipalatinsk Nuclear Test Site, Kazakhstan.

The issue of radiation exposure as a potential cause of cerebrovascular disease raises many concerns. The aim of the present study was to investigate the epidemiology of stroke and transient ischemic attacks (TIA) along with the associated risk factors among the population of East Kazakhstan exposed to ionising radiation from the former Semipalatinsk Nuclear Test Site (SNTS) in comparison with the unexposed population of the same region. This 5-year retrospective cross-sectional study included the data on 10,970 patients, of whom the majority (62.3%) suffered from ischemic stroke, 11.7% had hemorrhagic stroke and the remaining 26.0% had TIA. At the moment when stroke/TIA happened, exposed patients were younger than the unexposed (mean age 63 years versus 64 years, p < 0.001) and showed higher rates of nearly all associated comorbidities, which commonly were more severe. Besides, exposed patients showed a higher risk of stroke lethality in contrast with the unexposed. The observed features might indicate that people residing in the vicinity of the SNTS are vulnerable to cerebrovascular disease and thus, this study contributes to timely recognition of this public health problem. In addition, a longitudinal study has to be envisaged to clarify whether there is any cause-effect relationship between exposure to radiation from the SNTS and the development of stroke or transient ischemic attacks.

Cryptogenic Stroke and Embolic Stroke of Undetermined Source: Risk Factors and Approaches for Detection of Atrial Fibrillation.

BACKGROUND: Stroke is a problem worldwide because of its high mortality and disability rates. Almost 90% of strokes are ischemic, and more than half of the deaths are caused by an ischemic stroke. Most risk factors for stroke are manageable so that it can be avoided with proper prevention. Despite the success in determining the causes of stroke in recent years, selectively, the "culprit" causing stroke remains unsolved. In such cases, a diagnosis of undetermined etiology (cryptogenic stroke) or embolic stroke of undetermined source (ESUS) is generated, resulting the prevention of a recurrent cerebrovascular occurrence impossible. Atrial fibrillation (AF) can be a cause of stroke by causing blood clots in the chambers of the heart. PURPOSE: The aim was to determine the optimal method of heart rate monitoring in patients with ischemic stroke, as methods and approaches for detecting AF are very diverse, but there is still no single opinion, which would be universal. PROCEDURES: In our review, we consider epidemiology, risk factors for the stroke of undetermined etiology, as well as analytical methods for detecting heart rhythm disturbances in this category of patients. FINDINGS: Atrial fibrillation (AF) is detected by thorough monitoring of heart rate of patients with cryptogenic stroke and ESUS can be diagnosed in up to 46% of patients. . CONCLUSION: After AF detection, consideration should be given to prescribing anticoagulants, instead of antiplatelet agents, for the secondary prevention of stroke.

High-density mapping of multiple atypical atrial flutter. First HD GRID mapping experience among The Commonwealth of Independent States.

Mapping of multiple atrial tachycardias after previous cryoballoon pulmonary vein isolations and multiple radiofrequency ablations can be challenging even for experienced specialists. HD Grid high-density mapping catheter is one of the catheters, which helps not only to precisely identify the mechanisms of macro-reentry tachycardia but also to avoid unnecessary radiofrequency applications. Accordingly, we present two cases of complex atrial arrhythmia with the use of HD Grid, which showed clear visualization of mechanisms and target ablations with the termination of tachycardia.

Can chronotropic incompetence predict life-threatening ventricular arrhythmias in patients with stable ischemic heart disease?

BACKGROUND: Chronotropic incompetence has prognostic value of all-cause and cardiovascular mortality in both patients with asymptomatic and symptomatic ischemic heart disease (IHD), regardless of traditional risk factors. The aim of this study was to investigate the relationship between chronotropic response during exercise test and the development of ventricular arrhythmias. METHODS: 153 patients with stable ischemic heart disease were screened and observed during the 24 months since October 2014 in a university hospital in Astana Kazakhstan. They underwent bedside electrocardiography, 24h heart rate Holter monitoring, echocardiography, exercise stress test (treadmill) for assessment of chronotropic index calculating at first contact. Holter- electrocardiography was repeated three times (at 3, 6, 12 months of follow-up period) to reveal life-threatening ventricular arrhythmias. RESULTS: The quantity of the ventricular extrasystoles was higher in the group with low chronotropic index. Low chronotropic index increased the risk of high grade ventricular extrasystoles more than two times (P=0.015); episodes of non-sustained VT more than three times (p<0.001); and episodes of sustained VT more than nine times (p<0.001). CONCLUSIONS: Chronotropic index less than 35.6 increases the risk for life-threatening ventricular arrhythmias in patients with stable chronicle ischemic heart disease irrespectively of severe left ventricle systolic dysfunction.

RYR2 sequencing reveals novel missense mutations in a Kazakh idiopathic ventricular tachycardia study cohort.

Channelopathies, caused by disturbed potassium or calcium ion management in cardiac myocytes are a major cause of heart failure and sudden cardiac death worldwide. The human ryanodine receptor 2 (RYR2) is one of the key players tightly regulating calcium efflux from the sarcoplasmic reticulum to the cytosol and found frequently mutated (<60%) in context of catecholaminergic polymorphic ventricular tachycardia (CPVT1). We tested 35 Kazakhstani patients with episodes of ventricular arrhythmia, two of those with classical CPVT characteristics and 33 patients with monomorphic idiopathic ventricular arrhythmia, for variants in the hot-spot regions of the RYR2 gene. This approach revealed two novel variants; one de-novo RYR2 mutation (c13892A>T; p.D4631V) in a CPVT patient and a novel rare variant (c5428G>C; p.V1810L) of uncertain significance in a patient with VT of idiopathic origin which we suggest represents a low-penetrance or susceptibility variant. In addition we identified a known variant previously associated with arrhythmogenic right ventricular dysplasia type2 (ARVD2). Combining sets of prediction scores and reference databases appeared fundamental to predict the pathogenic potential of novel and rare missense variants in populations where genotype data are rare.

Sequence Alterations of I(Ks) Potassium Channel Genes in Kazakhstani Patients with Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most common sustained arrhythmia, and it results in significant morbidity and mortality. However, the pathogenesis of AF remains unclear to date. Recently, more pieces of evidence indicated that AF is a multifactorial disease resulting from the interaction between environmental factors and genetics. Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks)) may underlie AF. OBJECTIVE: To investigate sequence alterations of I(Ks) potassium channel genes KCNQ1, KCNE1 and KCNE2 in Kazakhstani patients with atrial fibrillation. METHODS: Genomic DNA of 69 cases with atrial fibrillation and 27 relatives were analyzed for mutations in all protein-coding exons and their flanking splice site regions of the genes KCNQ1 (NM_000218.2 and NM_181798.1), KCNE1 (NM_000219.2), and KCNE2 (NM_172201.1) using bidirectional sequencing on the ABI 3730xL DNA Analyzer (Applied Biosystems, Foster City, CA, USA). RESULTS: In total, a disease-causing mutation was identified in 39 of the 69 (56.5%) index cases. Of these, altered sequence variants in the KCNQ1 gene accounted for 14.5% of the mutations, whereas a KCNE1 mutation accounted for 43.5% of the mutations and KCNE2 mutation accounted for 1.4% of the mutations. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. We found two sequence variants in KCNQ1 exon 13 (S546S G1638A) and exon 16 (Y662Y, C1986T) in ten patients (14.5%). In KCNE1 gene in exon 3 mutation, S59G A280G was observed in 30 of 69 patients (43.5%) and KCNE2 exon 2 T10K C29A in 1 patient (1.4%). Genetic cascade screening of 27 relatives to the 69 index cases with an identified mutation revealed 26.9% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death. CONCLUSION: In this cohort of Kazakhstani index cases with AF, a disease-causing mutation was identified in 56.5 % of the referred patients. Further screening of mutations in other genes encoding cardiac ion channels is needed to clarify possible disease causing and founder mutations in Kazakhstani atrial fibrillation patients.