|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 8
| Issue : 1 | Page : 9-16 |
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Genetic targets in the management of atrial fibrillation in patients with cardiomyopathy
Michaela Zigova1, Eva Petrejčíková1, Marta Mydlárová Blaščáková1, Ján Kmec2, Jarmila Bernasovská1, Iveta Boroňová1, Martin Kmec2
1 Department of Biology, Faculty of Humanities and Natural Sciences, University of Prešov, Prešov, Slovakia
2 Cardiocentre of Faculty Hospital J. A. Reiman in Prešov, Prešov, Slovakia
| Date of Submission | 19-Nov-2021 |
| Date of Decision | 10-Feb-2022 |
| Date of Acceptance | 15-Mar-2022 |
| Date of Web Publication | 26-Apr-2022 |
Correspondence Address:
Michaela Zigova
Department of Biology, Faculty of Humanities and Natural Sciences, University of Prešov, Prešov
Slovakia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpcs.jpcs_65_21
Cardiomyopathies are heterogeneous health conditions with the potential for atrial fibrillation. The management of patients with cardiomyopathy accompanied by atrial fibrillation is complicated by the maintenance of sinus rhythm, toxicity, or other complications. There is a lack of information about the reasons for therapy response heterogeneity or therapy failure. Our searching strategy of scientific databases declares a potentially important role of genetics in patients' management. The promising target could be the 4q25 locus and its sequence variants. Molecular-genetic analyses may shed new light on anti-atrial fibrillation therapy in cardiomyopathy patients and help reveal the genetic subtypes of cardiomyopathy patients. In this sense, the purpose of our study is to examine the evidence for genetic variation influencing the efficacy of pharmacological or invasive therapies for atrial fibrillation, especially at the 4q25 locus, in cardiomyopathy patients and declare the importance of detected genetic markers responsible for positive or negative responses to specific anti-atrial fibrillation therapies.
Keywords: 4q25, atrial fibrillation, cardiomyopathy, PITX2 gene, recurrence, therapy response
How to cite this article:
Zigova M, Petrejčíková E, Blaščáková MM, Kmec J, Bernasovská J, Boroňová I, Kmec M. Genetic targets in the management of atrial fibrillation in patients with cardiomyopathy. J Pract Cardiovasc Sci 2022;8:9-16 |
How to cite this URL:
Zigova M, Petrejčíková E, Blaščáková MM, Kmec J, Bernasovská J, Boroňová I, Kmec M. Genetic targets in the management of atrial fibrillation in patients with cardiomyopathy. J Pract Cardiovasc Sci [serial online] 2022 [cited 2023 Mar 30];8:9-16. Available from: https://www.j-pcs.org/text.asp?2022/8/1/9/344134 |
| Introduction | |  |
Cardiomyopathy is a health complication associated with the activation of pathological processes in the myocardium that results in abnormal heart function, including atrial fibrillation.[1],[2] Cardiac arrhythmias, notably atrial fibrillation, are health conditions with an unfavorable prognosis that increases the risk of morbidity, hospitalization, and mortality, not only in cardiomyopathy patients. Atrial fibrillation can be considered a current epidemic of cardiovascular disease. The main negative effects of atrial fibrillation correspond to progression to chronic conditions, lower quality of life influenced by disease symptoms, treatment, and growing socioeconomic problems. Identified risk factors include older age, cardiomyopathy, and other causes of heart failure.[3],[4] Recent findings confirm the contribution of genetic factors in the pathogenesis and heterogeneity of atrial fibrillation and their potential role in disease management.[3],[5],[6],[7] The purpose of this article is to examine the evidence for genetic variation influencing the efficacy of anti-atrial fibrillation therapies and their potential to modulate recurrences in cardiomyopathy patients.
| Methodology | | |
A search strategy was chosen to detect relevant literary sources and examine the evidence for genetic variations associated with atrial fibrillation that influence the efficacy of invasive or pharmacologic therapies for atrial fibrillation, especially at the 4q25 locus. All relevant information was searched in scientific databases such as DisGeNET, MalaCards, NCBI, and PubMed. Cardiomyopathy, atrial fibrillation (including abbreviations AF and Afib), atrial fibrillation therapy (invasive and non-invasive), 4q25, PITX2, and recurrence were the keywords used in the search. A summary of associations was prepared according to data from the genome-wide association study (GWAS) Catalog (The NHGRI-EBI Catalog of human genome-wide association studies) after entering the keyword atrial fibrillation. From all the genetic loci, only sequence variants with odds ratios (ORs) greater than 1.2 were relevant for our article. If the variant had more than one OR, the one with the highest value was chosen.
| Some Facts about Atrial Fibrillation in Cardiomyopathy Patients | | |
Cardiomyopathies represent a heterogeneous group of heart diseases with characteristic nonischemic myocardial involvement.[7] Patients with cardiomyopathy may face a significant burden of arrhythmias, which often complicate the disease course. Arrhythmias may result from myocardial changes induced by cardiomyopathies, or, on the other hand, arrhythmias may be a cause of the development of cardiomyopathy-mediated phenotypes (arrhythmia-induced cardiomyopathies). Sinus tachycardia and supraventricular arrhythmias are common in patients with cardiomyopathy, in particular, atrial fibrillation.[1],[2],[7],[8],[9]
All cardiomyopathy types have distinct etiologies, features, outcomes, and prevalence, but there is some overlap at the genotype and phenotype levels.[2],[10]
The prevalence of atrial fibrillation in patients can vary according to cardiomyopathy type (ranging from 1% to 33% in adults).[2] The published annual incidence of de novo atrial fibrillation in some cardiomyopathy patients is 2% per year. On an average, atrial fibrillation is about five times more common in patients with hypertrophic cardiomyopathy than in the general population, and approximately 20%–32% of patients with this type of cardiomyopathy develop atrial fibrillation.[8],[11] Atrial fibrillation in this group of patients is highly symptomatic and accompanied by a higher risk of thromboembolism.[8] On the other hand, data showed that about 10% of patients with confirmed atrial fibrillation were diagnosed with some type of cardiomyopathy.[9],[12]
Increased emphasis in cardiovascular medicine is placed on age stratification, gender gap, and ethnic variability. Gender may modify disease outcomes resulting in various cardiomyopathy forms, such as disease prevalence, severity, prognosis, and treatment strategies. Most of the published cardiomyopathy cohorts have shown a male predominance. It can be expected that in the case of cardiomyopathies accompanied by atrial fibrillation, the male predominance will also be confirmed. However, these data may be overestimated because of the delayed onset of symptoms and diagnosis estimation in women. Gender, on the other hand, is associated with a poor prognosis of the disease in women.[13],[14],[15],[16]
The ethnic variability in both atrial fibrillation and cardiomyopathy was also recognized, but the frequency of cardiomyopathy accompanied by atrial fibrillation in variable ethnic groups is unpublished.[17],[18]
The main diagnostic complications are the asymptomatic course of atrial fibrillation and the estimation of early diagnosis. The percentage of asymptomatic patients is expected to be relatively high, which highlights the importance of population-wide screening. The next complication is connected to the fact that atrial fibrillation in cardiomyopathy patients is characterized by a high recurrence rate and unpredictable episodes of arrhythmia. The therapy of patients with cardiomyopathy accompanied by atrial fibrillation is similar to the therapy of other atrial fibrillation-associated diseases.[3],[19],[20]
The pathophysiological conditions that predispose to atrial fibrillation in cardiomyopathy patients are poorly understood. It is assumed that pathophysiological processes in cardiomyopathy form a substrate (arrhythmogenic, structural, architectural, contractile, or electrophysiological) associated with complications in patients. There are still no effective predictors of severe outcomes, new attacks, or disease recurrence.[1],[2],[3],[21]
Potentially, the pro-arrhythmogenic potential of cardiomyopathy may be rooted in the genetic background of the disease, and pathophysiological mechanisms will likely differ depending on the atrial fibrillation-affected genes. The molecular-genetic approach can provide important insights into the pathogenesis of atrial fibrillation in the context of cardiomyopathy, and the detection of potential genetic markers may be useful in outcome prediction, in the processes of identification of new genetic subtypes of atrial fibrillation, and in therapeutic strategies.[1],[2],[3],[5],[6],[21],[22]
| Pathophysiological Substrates of Atrial Fibrillation in Cardiomyopathy Patients | | |
Atrial fibrillation is a specific arrhythmia that manifests in many forms. Cardiomyopathies may be a secondary risk factor for atrial fibrillation. On the other hand, it is assumed that the mechanism of atrial fibrillation in patients with cardiomyopathy could be similar to mechanisms in other atrial fibrillation-associated diseases, but some specific factors may be involved in the development and progression of atrial fibrillation in this group of patients.[1],[2],[9],[21],[23]
The processes underlying atrial fibrillation are complex and not fully elucidated. In the pathogenesis of cardiomyopathy accompanied by atrial fibrillation, there are necessary multi-level changes. Essentially, atrial fibrillation evokes changes in electrophysiological properties within the atrial myocardium. Atrial electrical remodeling may predispose to increased susceptibility to new episodes. These changes can affect atrial mechanical functions and, ultimately, its ultrastructure. Atrial remodeling is determined by the mechanisms realized at a subcellular level. A trigger and anatomical substrate are necessary for the genesis and perpetuation of atrial fibrillation.[1],[2],[24] The initiation and maintenance processes of atrial fibrillation depend on the pathophysiological changes at the ion channels, cardiomyocytes, or tissue level. These changes contribute to structural, architectural, contractile, or electrophysiological remodeling accompanied by rapid and uncoordinated atrial action. Comorbidities increase individual patients' risk because of the potential to start and enhance the structural remodeling processes of atrial fibrillation, resulting in an electro-anatomical substrate that allows the maintenance of arrhythmia. Associated heart diseases, including cardiomyopathies, usually modify the natural course of atrial fibrillation. The main cardiomyopathy features such as atrial fibrosis, cardiomyocyte disarray, and necrosis are major proarrhythmogenic substrates relating to atrial remodeling and subsequent abnormal atrial contraction. Regular atrial contraction is necessary for left ventricular filling and function in cardiomyopathy patients. Tissue remodeling can lead to fibrosis, which fixes arrhythmia, but the probability of restoring the sinus rhythm is decreasing. For this reason, the disease may progress to severe or chronic forms.[8],[25],[26]
In the described processes, multiple molecules, signaling pathways, and risk factors can be implicated. Nowadays, in the “molecular-genetic era,” scientists try to confirm the role of genetic background in the pathogenesis of cardiomyopathy accompanied by atrial fibrillation.[2],[21],[27] The potential role of selected genes and their variants was detected in inherited arrhythmia syndromes (Brugada syndrome, long QT syndrome, and in patients with familial cardiomyopathy), as well as in patients with sporadic arrhythmia complications. Monogenic forms of atrial fibrillation with rare genetic variants are less frequent than phenotypes caused by common genetic variants. A variety of risk factors, including genetic heterogeneity, can increase susceptibility to the disease onset and course of atrial fibrillation and other cardiomyopathy-associated complications.[2],[21],[28],[29],[30]
The portfolio of implicated genes may differ according to the disease subtype. Scientists have detected more than a hundred loci with the potential to contribute to atrial fibrillation pathogenesis and outcome. Many atrial fibrillation loci overlap with known loci for cardiomyopathy and could contribute to atrial fibrillation symptomatology in this group of patients. The main genetic substrate associated with cardiomyopathy encodes sarcomere, Z-disk, cytoskeleton, and ion channel proteins with an important role in myocardial contraction. The exact role of genes and genetic variations in the mechanisms underlying atrial fibrillation is unknown.[27],[29],[31] Predicted loci with large effect sizes are 5p13, 6q14-16, 7q35-36, 10q22-24, 11p15.5, 17q, and 21q22.[32] According to the list of risk loci, we can predict that known genes involved in atrial fibrillation pathogenesis are related to ion channels, mechanisms of calcium homeostasis, cardiogenesis, fibrosis formation, extracellular matrix remodeling, cardiac contraction, cell-to-cell coupling, inflammatory pathways, etc. Except for the main candidate genes, GWAS identified additional genes and some common variants associated with atrial fibrillation [Table 1]. The most interesting regions that are significantly associated with atrial fibrillation are the genetic loci 1q21, 4q25, and 16q22, which may also be potential intervention targets.[25],[44] The variability of implicated genes indicates that multiple mechanisms can contribute to atrial fibrillation susceptibility. | Table 1: Genome-wide association studies results for atrial fibrillation
Click here to view |
| Pitfalls in Patient Management | | |
Genetic testing is not a routine approach in the management of atrial fibrillation patients. If this approach is applied, genetic testing is recommended in the diagnostic process, but not in therapeutic strategies. The targeted, correct, and prompt management of cardiomyopathy patients, especially those with a higher risk of atrial fibrillation complications, is a crucial task for clinicians. Nowadays, several publications have reported the importance of genetic testing not only in the diagnosis but also in the treatment of multiple diseases, including atrial fibrillation.[22],[45] The normalization of heart rhythm, the suppression of arrhythmia episodes, the prevention of heart failure, and thromboembolism in patients with atrial fibrillation are great challenges. The progressive nature of atrial fibrillation depends on the management of disease complications and targeted treatment. Pharmacotherapy is the mainstay of atrial fibrillation treatment.[46] The pharmacological management of atrial fibrillation is difficult due to the maintenance of sinus rhythm, toxicity, or other complications. In a lot of cases, therapy is unsuccessful, and the arrhythmia remains fixed in patients. Unsatisfactory results of pharmacotherapy have stimulated the development of nonpharmacological treatment approaches, but hybrid treatment is also a promising strategy to eliminate disease complications. Despite this, the occurrence of relapses remains relatively high.[3],[19],[20]
Different atrial fibrillation substrates in cardiomyopathy patients may be responsible for the significantly lower efficacy of anti-atrial fibrillation therapy in comparison to patients without cardiomyopathy. The long-term prognosis is influenced by the development of heart failure and thromboembolism.[1],[46]
In the context of atrial fibrillation as a cardiovascular epidemic, this condition develops and subsequently recurs in a relatively large number of patients. Relapses of atrial fibrillation after the previous appearance depend on multiple factors and may have a key role in a patient's long-term management. There is no rule that says the patient after the first episode of atrial fibrillation must conditionally have another episode. It is also questionable when the next episode of atrial fibrillation will occur. Information about the reasons for therapy failure and patient response heterogeneity is missing.[47] Recurrence incidence varies and depends on multiple factors, including the type of clinical intervention. Atrial fibrillation patients without antiarrhythmic intervention had a higher risk of recurrence in the 1st year (71%–84%). This recurrence risk can be reduced by 17%–27% after adequate medication.[48] Based on the used technique, the recurrence rate in patients after catheter ablation is predicted to be in the range of 20%–60%.[6] Many atrial fibrillation recurrences also occur after electrical cardioversion. A large number of them appear within a month of cardioversion.[49] Scientific data demonstrate that heart changes caused by cardiomyopathies may be a prerequisite for therapy failure and a new episode of atrial fibrillation occurrence. Hence, the recurrence risk in cardiomyopathy patients may be higher compared to controls. That may be the reason for repeated clinical intervention in patients with cardiomyopathy.[50] Dinshaw et al. confirmed the recurrences of atrial fibrillation in patients with hypertrophic cardiomyopathy after ablation, with a recurrence rate of 38% at 4 years after 1.9 ± 1.2 procedures.[51]
Understanding the mechanisms underlying atrial fibrillation in cardiomyopathy patients is a key task in clarifying the success of the therapy. Thus, it could be hypothesized that specific genes causing cardiomyopathy may differentially promote atrial fibrillation occurrence. The variability of implicated genes could be potentially associated with a difference in the response of patients to therapy and therapeutic success. Prediction of a patient's genetic status could be a potential way to determine the optimal management of cardiomyopathy patients. Then early and targeted treatment processes could lead to the prolongation of an active life and improve its quality.[22],[45],[52],[53]
We believe that the molecular-genetic approach in atrial fibrillation patients could elucidate these complications, and that genetic testing in patients with atrial fibrillation could improve the effectiveness of the postdiagnostic process, optimize therapy, and try to identify genetic subtypes of disease with differential responses to therapy.
| Potential Genetic Target for Cardiomyopathy Patients | | |
Recent studies point to a genotype-dependent response to atrial fibrillation therapy in patients. One of the potential genotyping targets is a specific locus, 4q25, near the PITX2 gene [Table 2]. | Table 2: The evidence of the relationship between anti-atrial fibrillation therapy and locus 4q25
Click here to view |
The data suggest that risk alleles of the locus 4q25 occur in approximately one-quarter of European ancestry individuals, which may be a reason for the impaired clinical response to anti-atrial fibrillation therapy.[54],[55] Single-nucleotide polymorphisms detected in this locus could be potential modulators of treatment response, including the response to the antiarrhythmic drug.[5],[6],[7],[22],[55],[58] Locus 4q25 represents an intronic sequence on chromosome 4 near the PITX2 gene, which is one of the most frequently reported genes for its implication in atrial fibrillation pathogenesis. The locus spans a region that includes genetic variants, potentially serving as modulators of paired-like homeodomain transcription factor 2 encoded by the PITX2 gene. Nonprotein coding sequences, which are 1.5 Mb upstream of the PITX2 gene, are considered a gene desert, but conserved sequences of the locus 4q25 are involved in the transcriptional regulation of the PITX2 gene. A potential mechanism that may lead to a different response to therapy is the influence of the expression of the PITX2 gene.[25],[71],[72] The PITX2 gene is in the GeneCards database registered as a protein-coding gene with genomic location chr4:110,617,423-110,642,123 (GRCh38/hg38). The PITX2 gene encodes three different isoforms, Pitx2a, Pitx2b, and Pitx2c, members of the RIEG/PITX homeobox family, which are transcription factors involved in several human disorders, including atrial fibrillation. The function of Pitx2 is conserved in vertebrates. The cardiac isoform of the cardiac paired-like homeodomain transcription factor 2 is predominantly expressed in the left atrium. The abnormal expression of the cardiac isoform, which is crucial in early cardiac development and morphogenesis, has been associated with an increased predisposition to atrial fibrillation.[73] In the pathogenesis of atrial fibrillation, the isoform Pitx2c relates to atrial structural and electrical remodeling by indirectly atrial fibrillation, affecting WNT signaling, which is important in the process of fibrosis formation, the main hallmark and mediator of atrial fibrillation in cardiomyopathy patients.[74],[75]
In this context, the specific polymorphisms of the locus 4q25 could also be potential modulators of response to therapy in patients with cardiomyopathy. The optimal medication could be dependent on the specific genotype of the patient. These hypotheses lead to the idea of the implication of genetic testing in predicting a patient's response to therapy for atrial fibrillation and to individualization of therapeutical approaches for cardiomyopathy patients. The clue task is to detect patients with a positive and negative response to adequate anti-atrial fibrillation therapy and to determine combinations of alleles, genotypes, or haplotypes with better outcomes for atrial fibrillation after adequate therapy. Whereas the important question is whether the genetic variants act independently or in combination with each other. There is limited information about this topic, and some of it is controversial.[5],[54],[55],[56],[57]
This opens space for possible stratification of therapeutic approaches by genotypes and active search for genetic subtypes of atrial fibrillation with different responses to therapy and disease recurrence.
| Conclusion | | |
Strategies for heart rhythm management in cardiomyopathy patients may have shortcomings that arise due to a lack of knowledge of atrial fibrillation pathogenesis in these patients. Prompt anti-atrial fibrillation therapy is required, but it can be accompanied by limited effectiveness because of early relapses. The molecular-genetic analyses may shed new light on atrial fibrillation therapy complications not only in cardiomyopathy patients. This approach is complicated by a lot of limitations, such as detected loci but missing responsible genes, a lot of implicated genes, unclear links between the genetic background of cardiomyopathy and atrial fibrillation, lack of distinction between benign and pathological genetic variants, variants with small effect sizes, therapy shortcomings, complicated translation of molecular-genetic results into medical practice, and others. However, all these limitations open space for a deeper study and understanding of cardiomyopathy subtypes, pathogenesis, and different responses to anti-atrial fibrillation therapy.
Financial support and sponsorship
Independent Scientific Grant Pfizer, grant number ID 56862787 supported the study.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Qin D, Mansour MC, Ruskin JN, Heist EK. Atrial fibrillation-mediated cardiomyopathy. Circ Arrhythm Electrophysiol 2019;12:e007809.  |
| 2. | Yeung C, Enriquez A, Suarez-Fuster L, Baranchuk A. Atrial fibrillation in patients with inherited cardiomyopathies. Europace 2019;21:22-32. |
| 3. | Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373-498. |
| 4. | Zaidi AM, Ahmed MJ, Bakibillah AS. Feature Extraction and Characterization of Cardiovascular Arrhythmia and Normal Sinus Rhythm from ECG Signals Using LabVIEW. 2017 IEEE International Conference on Imaging, Vision & Pattern Recognition (icIVPR), Dhaka, Bangladesh; 2017. p. 1-6. |
| 5. | Jiang T, Wang YN, Qu Q, Qi TT, Chen YD, Qu J. Association between gene variants and the recurrence of atrial fibrillation: An updated meta-analysis. Medicine (Baltimore) 2019;98:e15953. |
| 6. | Rattanawong P, Chenbhanich J, Vutthikraivit W, Chongsathidkiet P. A chromosome 4q25 variant is associated with atrial fibrillation recurrence after catheter ablation: A systematic review and meta-analysis. J Atr Fibrillation 2018;10:1666. |
| 7. | Sisakian H. Cardiomyopathies: Evolution of pathogenesis concepts and potential for new therapies. World J Cardiol 2014;6:478-94. |
| 8. | Patten M, Pecha S, Aydin A. Atrial fibrillation in hypertrophic cardiomyopathy: Diagnosis and considerations for management. J Atr Fibrillation 2018;10:1556. |
| 9. | Bonadei I, Gorga E, Lombardi C, Metra M. Arrhythmias and cardiomyopathy: When arrhythmias come first. J Cardiovasc Med (Hagerstown) 2017;18 Suppl 1:e145-8. |
| 10. | Glaveckaitė S, Mikštienė V, Preikšaitienė E, Norvilas R, Janavičius R, Valevičienė NR. Overlapping phenotype of cardiomyopathy in a patient with double mutation: A case report. Cardiogenetics 2021;11:31-8. |
| 11. | Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e783-831. |
| 12. | Camm CF, Camm AJ. Atrial fibrillation and anticoagulation in hypertrophic cardiomyopathy. Arrhythm Electrophysiol Rev 2017;6:63-8. |
| 13. | Meyer S, van der Meer P, van Tintelen JP, van den Berg MP. Sex differences in cardiomyopathies. Eur J Heart Fail 2014;16:238-47. |
| 14. | Pothineni NV, Vallurupalli S. Gender and atrial fibrillation: Differences and disparities. US Cardiol Rev 2018;1:103-6. |
| 15. | Siontis KC, Ommen SR, Geske JB. Sex, survival, and cardiomyopathy: Differences between men and women with hypertrophic cardiomyopathy. J Am Heart Assoc 2019;8:e014448. |
| 16. | Ko D, Rahman F, Schnabel RB, Yin X, Benjamin EJ, Christophersen IE. Atrial fibrillation in women: Epidemiology, pathophysiology, presentation, and prognosis. Nat Rev Cardiol 2016;13:321-32. |
| 17. | Amponsah MK, Benjamin EJ, Magnani JW. Atrial fibrillation and race – A contemporary review. Curr Cardiovasc Risk Rep 2013;7:366-45. |
| 18. | Eberly LA, Day SM, Ashley EA, Jacoby DL, Jefferies JL, Colan SD, et al. Association of race with disease expression and clinical outcomes among patients with hypertrophic cardiomyopathy. JAMA Cardiol 2020;5:83-91. |
| 19. | Tian T, Wang Y, Sun K, Wang J, Zou Y, Zhang W, et al. Clinical profile and prognostic significance of atrial fibrillation in hypertrophic cardiomyopathy. Cardiology 2013;126:258-64. |
| 20. | Wilke I, Witzel K, Münch J, Pecha S, Blankenberg S, Reichenspurner H, et al. High incidence of de novo and subclinical atrial fibrillation in patients with hypertrophic cardiomyopathy and cardiac rhythm management device. J Cardiovasc Electrophysiol 2016;27:779-84. |
| 21. | Andersen JH, Olesen MS. Genetics of atrial fibrillation and atrial cardiomyopathy. J Hum Clin Gen 2019;1:1-3. |
| 22. | Darbar D. The role of pharmacogenetics in atrial fibrillation therapeutics: Is personalized therapy in sight? J Cardiovasc Pharmacol 2016;67:9-18. |
| 23. | Seko Y, Kato T, Haruna T, Izumi T, Miyamoto S, Nakane E, et al. Association between atrial fibrillation, atrial enlargement, and left ventricular geometric remodeling. Sci Rep 2018;8:6366. |
| 24. | Rosenberg MA, Manning WJ. Diastolic dysfunction and risk of atrial fibrillation: A mechanistic appraisal. Circulation 2012;126:2353-62. |
| 25. | Lozano-Velasco E, Franco D, Aranega A, Daimi H. Genetics and epigenetics of atrial fibrillation. Int J Mol Sci 2020;21:5717. |
| 26. | Zhou X, Dudley SC Jr. Evidence for inflammation as a driver of atrial fibrillation. Front Cardiovasc Med 2020;7:62. |
| 27. | Fatkin D, Huttner IG, Johnson R. Genetics of atrial cardiomyopathy. Curr Opin Cardiol 2019;34:275-81. |
| 28. | Tzou WS, Gerstenfeld EP. Genetic testing in the management of inherited arrhythmia syndromes. Curr Cardiol Rep 2009;11:343-51. |
| 29. | McNally EM, Mestroni L. Dilated cardiomyopathy: Genetic determinants and mechanisms. Circ Res 2017;121:731-48. |
| 30. | Mahida S, Lubitz SA, Rienstra M, Milan DJ, Ellinor PT. Monogenic atrial fibrillation as pathophysiological paradigms. Cardiovasc Res 2011;89:692-700. |
| 31. | Jacoby D, McKenna WJ. Genetics of inherited cardiomyopathy. Eur Heart J 2012;33:296-304. |
| 32. | Chia R, Mehta A, Huang H, Darbar D. Genetic atrial fibrillation. In: Vasan RS, Sawyer DB, editors. Encyclopedia of Cardiovascular Research and Medicine. USA: Elsevier; 2018. p. 303-12. |
| 33. | Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM, et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet 2018;50:1225-33. |
| 34. | Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010;42:240-4. |
| 35. | Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009;41:879-81. |
| 36. | Nielsen JB, Fritsche LG, Zhou W, Teslovich TM, Holmen OL, Gustafsson S, et al. Genome-wide study of atrial fibrillation identifies seven risk loci and highlights biological pathways and regulatory elements involved in cardiac development. Am J Hum Genet 2018;102:103-15. |
| 37. | Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, et al. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet 2017;49:946-52. |
| 38. | Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44:670-5. |
| 39. | Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009;41:876-8. |
| 40. | Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham SE, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet 2018;50:1234-9. |
| 41. | Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007;448:353-7. |
| 42. | Kertai MD, Li YJ, Ji Y, Qi W, Lombard FW, Shah SH, et al. Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery. Am Heart J 2015;170:580-90.e28. |
| 43. | Weng LC, Choi SH, Klarin D, Smith JG, Loh PR, Chaffin M, et al. Heritability of atrial fibrillation. Circ Cardiovasc Genet 2017;10:e001838.8. |
| 44. | Hong K, Xiong Q. Genetic basis of atrial fibrillation. Curr Opin Cardiol 2014;29:220-6. |
| 45. | Moaddeb J, Haga SB. Pharmacogenetic testing: Current evidence of clinical utility. Ther Adv Drug Saf 2013;4:155-69. |
| 46. | Batul SA, Gopinathannair R. Atrial fibrillation in heart failure: A therapeutic challenge of our times. Korean Circ J 2017;47:644-62. |
| 47. | Simantirakis EN, Papakonstantinou PE, Kanoupakis E, Chlouverakis GI, Tzeis S, Vardas PE. Recurrence rate of atrial fibrillation after the first clinical episode: A prospective evaluation using continuous cardiac rhythm monitoring. Clin Cardiol 2018;41:594-600. |
| 48. | Vizzardi E, Curnis A, Latini MG, Salghetti F, Rocco E, Lupi L, et al. Risk factors for atrial fibrillation recurrence: A literature review. J Cardiovasc Med (Hagerstown) 2014;15:235-53. |
| 49. | Tieleman RG, Van Gelder IC, Crijns HJ, De Kam PJ, Van Den Berg MP, Haaksma J, et al. Early recurrences of atrial fibrillation after electrical cardioversion: A result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol 1998;31:167-73. |
| 50. | Providencia R, Elliott P, Patel K, McCready J, Babu G, Srinivasan N, et al. Catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: A systematic review and meta-analysis. Heart 2016;102:1533-43. |
| 51. | Dinshaw L, Münkler P, Schäffer B, Klatt N, Jungen C, Dickow J, et al. Ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy: Treatment strategy, characteristics of consecutive atrial tachycardia and long-term outcome. J Am Heart Assoc 2021;10:e017451. |
| 52. | Bassiouny M, Lindsay BD, Lever H, Saliba W, Klein A, Banna M, et al. Outcomes of nonpharmacologic treatment of atrial fibrillation in patients with hypertrophic cardiomyopathy. Heart Rhythm 2015;12:1438-47. |
| 53. | Bongini C, Ferrantini C, Girolami F, Coppini R, Arretini A, Targetti M, et al. Impact of genotype on the occurrence of atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol 2016;117:1151-9. |
| 54. | Husser D, Adams V, Piorkowski C, Hindricks G, Bollmann A. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2010;55:747-53. |
| 55. | Parvez B, Vaglio J, Rowan S, Muhammad R, Kucera G, Stubblefield T, et al. Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. J Am Coll Cardiol 2012;60:539-45. |
| 56. | Parvez B, Shoemaker MB, Muhammad R, Richardson R, Jiang L, Blair MA, et al. Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. Heart Rhythm 2013;10:849-55. |
| 57. | Benjamin Shoemaker M, Muhammad R, Parvez B, White BW, Streur M, Song Y, et al. Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation. Heart Rhythm 2013;10:394-400. |
| 58. | Goyal SK, Wang L, Upender R, Darbar D, Monahan K. Severity of obstructive sleep apnea influences the effect of genotype on response to anti-arrhythmic drug therapy for atrial fibrillation. J Clin Sleep Med 2014;10:503-7. |
| 59. | Roberts JD, Hsu JC, Aouizerat BE, Pullinger CR, Malloy MJ, Kane JP, et al. Impact of a 4q25 genetic variant in atrial flutter and on the risk of atrial fibrillation after cavotricuspid isthmus ablation. J Cardiovasc Electrophysiol 2014;25:271-7. |
| 60. | Choi EK, Park JH, Lee JY, Nam CM, Hwang MK, Uhm JS, et al. Korean Atrial Fibrillation (AF) Network: Genetic variants for AF do not predict ablation success. J Am Heart Assoc 2015;4:e002046. |
| 61. | Shoemaker MB, Bollmann A, Lubitz SA, Ueberham L, Saini H, Montgomery J, et al. Common genetic variants and response to atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2015;8:296-302. |
| 62. | Hu YF, Wang HH, Yeh HI, Lee KT, Lin YJ, Chang SL, et al. Association of single nucleotide polymorphisms with atrial fibrillation and the outcome after catheter ablation. Acta Cardiol Sin 2016;32:523-31. |
| 63. | Chen F, Yang Y, Zhang R, Zhang S, Dong Y, Yin X, et al. Polymorphism rs2200733 at chromosome 4q25 is associated with atrial fibrillation recurrence after radiofrequency catheter ablation in the Chinese Han population. Am J Transl Res 2016;8:688-97. |
| 64. | Kiliszek M, Kozluk E, Franaszczyk M, Lodzinski P, Piatkowska A, Ploski R, et al. The 4q25, 1q21, and 16q22 polymorphisms and recurrence of atrial fibrillation after pulmonary vein isolation. Arch Med Sci 2016;12:38-44. |
| 65. | Zhao LQ, Zhang GB, Wen ZJ, Huang CK, Wu HQ, Xu J, et al. Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population. Int J Cardiol 2017;227:360-6. |
| 66. | Miyazaki S, Ebana Y, Liu L, Nakamura H, Hachiya H, Taniguchi H, et al. Chromosome 4q25 variants and recurrence after second-generation cryoballoon ablation in patients with paroxysmal atrial fibrillation. Int J Cardiol 2017;244:151-7. |
| 67. | He J, Zhu W, Yu Y, Hu J, Hong K. Variant rs2200733 and rs10033464 on chromosome 4q25 are associated with increased risk of atrial fibrillation after catheter ablation: Evidence from a meta-analysis. Cardiol J 2018;25:628-38. |
| 68. | Choi JI, Baek YS, Roh SY, Piccini JP, Kim YH. Chromosome 4q25 variants and biomarkers of myocardial fibrosis in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2019;30:1904-13. |
| 69. | Choe WS, Kang JH, Choi EK, Shin SY, Lubitz SA, Ellinor PT, et al. A genetic risk score for atrial fibrillation predicts the response to catheter ablation. Korean Circ J 2019;49:338-49. |
| 70. | Wong GR, Nalliah CJ, Lee G, Voskoboinik A, Prabhu S, Parameswaran R, et al. Genetic susceptibility to atrial fibrillation is associated with atrial electrical remodeling and adverse post-ablation outcome. JACC Clin Electrophysiol 2020;6:1509-21. |
| 71. | Nobrega MA, Ovcharenko I, Afzal V, Rubin EM. Scanning human gene deserts for long-range enhancers. Science 2003;302:413. |
| 72. | Volkmann BA, Zinkevich NS, Mustonen A, Schilter KF, Bosenko DV, Reis LM, et al. Potential novel mechanism for Axenfeld-Rieger syndrome: Deletion of a distant region containing regulatory elements of PITX2. Invest Ophthalmol Vis Sci 2011;52:1450-9. |
| 73. | Kirchhof P, Kahr PC, Kaese S, Piccini I, Vokshi I, Scheld HH, et al. PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet 2011;4:123-33. |
| 74. | Lozano-Velasco E, Hernández-Torres F, Daimi H, Serra SA, Herraiz A, Hove-Madsen L, et al. Pit×2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling. Cardiovasc Res 2016;109:55-66. |
| 75. | Aguirre LA, Alonso ME, Badía-Careaga C, Rollán I, Arias C, Fernández-Miñán A, et al. Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP. BMC Biol 2015;13:26. |
[Table 1], [Table 2]
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