Background: Atrial fibrillation (AF) is the most common arrhythmia and typically occurs in elderly patients with other cardiovascular and extracardiac diseases. However, up to 15% of AF develops without any related risk factors. Recently, the role of genetic factors has been highlighted in this particular form of AF. Aims: The aims of this study were to determine the prevalence of pathogenic variants in early-onset AF in patients without known disease-related risk factors and to identify any structural cardiac abnormalities in these patients. Materials and Methods: We conducted exome sequencing and interpretation in 54 risk factor-free early-onset AF patients and further validated our findings in a similar AF patient cohort from the UK Biobank. Results: Pathogenic/likely pathogenic variants were found in 13/54 (24%) patients. The variants were identified in cardiomyopathy-related and not arrhythmia-related genes. The majority of the identified variants were TTN gene truncating variants (TTNtvs) (9/13 (69%) patients). We also observed two TTNtvs founder variants in the analysed population—c.13696C>T p.(Gln4566Ter) and c.82240C>T p.(Arg27414Ter). Pathogenic/likely pathogenic variants were found in 9/107 (8%) individuals from an independent similar AF patient cohort from the UK Biobank. In correspondence with our Latvian patients, only variants in cardiomyopathy-associated genes were identified. In five (38%) of the thirteen Latvian patients with pathogenic/likely pathogenic variants, dilation of one or both ventricles was identified on a follow-up cardiac magnetic resonance scan. Conclusions: We observed a high prevalence of pathogenic/likely pathogenic variants in cardiomyopathy-associated genes in patients with risk factor-free early-onset AF. Moreover, our follow-up imaging data indicate that these types of patients are at risk of developing ventricular dilation. Furthermore, we identified two TTNtvs founder variants in our Latvian study population.

Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT)-SNVs might present one potential source of this “missing heritability”. Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD = 20,405), and a more inclusive (angina and chronic ischemic heart disease; SOFT = 34,782). Results: In HARD cases, the most significant (p < 0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR = 1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR = 0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing corrections (at FDR < 5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active, and their average body height was ~2.00 cm lower compared to controls; both traits are known to be related to increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (p < 0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3), and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (p < 0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT-SNV data in even larger study cohorts may be needed to conclusively determine the role of MT DNA in CAD.

Background and Objectives: Recurrence of atrial fibrillation (AF) within six months after sinus rhythm restoration with direct current cardioversion (DCC) is a significant treatment challenge. Currently, the factors influencing outcome are mostly unknown. Studies have found a link between genetics and the risk of AF and efficacy of rhythm control. The aim of this study was to examine the association between eight single-nucleotide variants (SNVs) and the risk of AF development and recurrence after DCC. Materials and Methods: Regarding the occurrence of AF, 259 AF cases and 108 controls were studied. Genotypes for the eight SNVs located in the genes CAV1, MYH7, SOX5, KCNN3, ZFHX3, KCNJ5 and PITX2 were determined using high-resolution melting analysis and confirmed with Sanger sequencing. Six months after DCC, a telephone interview was conducted to determine whether AF had recurred. A polygenic risk score (PRS) was calculated as the unweighted sum of risk alleles. Multivariate regression analyses were performed to assess SNV and PRS association with AF occurrence and recurrence after DCC. Results: The risk allele of rs2200733 (PITX2) was significantly associated with the development of AF (p = 0.012, OR = 2.31, 95% CI = 1.206–4.423). AF recurred in 60% of patients and the allele generally associated with a decreased risk of AF of rs11047543 (SOX5) was associated with a greater risk of AF recurrence (p = 0.014, OR = 0.223, 95% CI = 0.067–0.738). A PRS of greater than 7 was significantly associated (p = 0.008) with a higher likelihood of developing AF after DCC (OR = 4.174, 95% CI = 1.454–11.980). Conclusions: A higher PRS is associated with increased odds of AF recurrence after treatment with DCC. PITX2 (rs2200733) is significantly associated with an increased risk of AF. The protective allele of rs11047543 (SOX5) is associated with a greater risk of AF recurrence. Further studies are needed to predict the success of rhythm control and guide patient selection towards the most efficacious treatment.

Atrial fibrillation (AF), the most common type of arrhythmia, has a heritable component. Variants at locus 4q25 are best associated with the risk of AF development in genome-wide association studies. Left atrial volume is an independent predictor of recurrence of AF after successful sinus rhythm restoration. The aim of our study was to investigate potential association between genetic variants at 4q25 locus and the risk of AF and echocardiographic parameters. We included 241 AF patients and 119 control individuals into the study. Left ventricle ejection fraction (LVEF, %) and left atrial volume index (LAVI, ml/m ² ) were assessed by transthoracic echocardiography during outpatient visits. We selected five 4q25 genetic variants (rs6825911, rs1126483, rs10004516, rs6838973, rs2200733) for the analysis. Variant rs6838973 was found to be associated with reduced risk of AF in additive (CCTT) and dominant (CC vs. CT+TT) models of inheritance. On the other hand, additive (CC<CT<TT) and dominant (CC vs. CT+TT) models of rs2200733 were associated with greater risk of AF. The same variations were found to be associated with age of AF onset. Median LAVI was 39.0 ml/m ² (IQR = 10.0) and median LVEF was 56.0% (IQR = 13.0). Statistically significant association was observed only between LAVI and variant rs1126483 in the dominant model of inheritance (median LAVI in CC vs. CT+TT – 38 ml/m ² vs. 40 ml/m ² , U = 1602.5, p = 0.032). No significant association was found for LVEF and the analysed genotypes.

Background: Up to 10% of atrial fibrillation (Afib) patients develop the condition in the young age and in the absence of any related risk factors. Recent publications emphasized the importance of genetic testing in this population. However, the yield of the investigation is highly variable and ranges from 1 to 24% precents. Purpose: The purpose of this study is to evaluate the prevalence of causative genetic variants in young Afib patients without risk factors and evaluate any structural changes of the heart. Methods: We performed whole exome sequencing in 54 young (age of Afib onset less than 65 years) Afib patients without any Afib related risk factors (original cohort). Using ACMG guidelines we performed analysis of 349 previously described cardiomyopathy and arrhythmia associated genes. If a pathogenic (P) or likely pathogenic (LP) variant was found, a cardiac magnetic resonance imaging (CMR) was performed to exclude any structural abnormalities of the heart. We also extracted 107 young Afib patients without any risk factors from UK Biobank (UK Biobank cohort) and performed analysis of the same genes in the subgroup. Results: The prevalence of P and LP variants was 24% (13 cases) in the original cohort and 8% (9 cases) in the UK Biobank cohort (p=0.006). We observed variants in cardiac structural and developmental genes only in both cohorts (Table 1 and 2). In the original cohort there were nine (17%) patients with P and LP variant in TTN gene. Moreover, five patients were positive for the same TTN variant NM_001267550.2:c.13696C>T p.(Gln4566Ter). In six (46%) original cohort patients we observed structural changes of the heart on CMR – in five patients there was dilation of one or both ventricles and in one there was increased T1 mapping intensity of septal wall segments. Conclusions: 1. There is a high prevalence of pathogenic and likely pathogenic causative genetic variants in young atrial fibrillation patients without any risk factors. 2. All variants are localized in cardiac structural or developmental genes only. 3. There is a high grade of structural changes of the heart observed on cardiac magnetic resonance imaging in patients with monogenic atrial fibrillation.Table 1.WES data in original cohortTable 2.WES data in UK Biobank cohort