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 Table of Contents  
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 9-16

Genetic targets in the management of atrial fibrillation in patients with cardiomyopathy

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 Submission19-Nov-2021
Date of Decision10-Feb-2022
Date of Acceptance15-Mar-2022
Date of Web Publication26-Apr-2022

Correspondence Address:
Michaela Zigova
Department of Biology, Faculty of Humanities and Natural Sciences, University of Prešov, Prešov
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcs.jpcs_65_21

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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 Top

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 Top

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 Top

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 Top

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

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  Pitfalls in Patient Management Top

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 Top

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

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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 Top

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.

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  [Table 1], [Table 2]


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