95c004552bc818b4ae11aa88a67f1531 335908.pdf 8ae98f89f6c30e96f8169f5df1428498402c574b 335908.pdf d1311c2f7fade029a98d6cabefa1b0cd33702c7d112b0cb7306755e97f128918 335908.pdf Title: Single-Nucleotide Polymorphisms, PITX2 and Abnormal Electrical Activity in Atrial Fibrillation Subject: Since single-nucleotide polymorphisms (SNPs) associated with increased risk of atrial fibrillation (AF) on chromosome 4q25 are located near the transcription factor PITX2, research has investigated relationships between SNPs, PITX2 activity and atrial function to improve risk stratification and identify new therapies. Although PITX2 levels are heterogeneous, most studies converge towards lower PITX2 levels in patients with AF, and a 4q25 SNP has been reported to reduce PITX2 expression. However, there are several SNPs at 4q25 that segregate independently, and patients carrying different SNPs respond differently to ablation therapy. On the other hand, atrial-specific deletion of Pitx2c mimics molecular and electrophysiological alterations observed in patients with AF. This includes microRNAs, signaling pathways, ion channels, calcium homeostasis, electrical remodeling, contraction and the response to pharmacological treatments. Moreover, mutations in the PITX2 homeodomain are associated with AF, PITX2 dysfunction or impaired calcium homeostasis. Interestingly, myocytes with the 4q25 risk allele rs13143308T display electrophysiological alterations similar to those reported in patients with AF or mice with heterozygous Pitx2c deletion. Moreover, carriers of rs13143308T respond poorly to ablation or antiarrhythmic drug therapy. Future research needs to establish how different 4q25 SNPs impact different PITX2 isoforms and the downstream regulation of atrial function. Keywords: Atrial arrhythmogenesis; PITX2 signaling pathways; genetic regulation; 4q25 risk variants; personalized medicine; ablation- and pharmacotherapy; cardiomyocyte function; calcium homeostasis; electrophysiology Author: Verónica Jiménez-Sábado and Leif Hove-Madsen Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Tue Oct 14 10:28:55 2025 CEST ModDate: Tue Oct 14 10:37:30 2025 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1697605 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZPTNWX+URWPalladioL-Roma Type 1 Custom yes yes yes 149 0 DHNMJD+URWPalladioL-Ital Type 1 Custom yes yes yes 150 0 SYCOIG+URWPalladioL-BoldItal Type 1 Custom yes yes yes 151 0 RRBYLY+URWPalladioL-Bold Type 1 Custom yes yes yes 152 0 EJNNLN+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 186 0 EJNNJM+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 187 0 EJNNLM+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 188 0 VDWKPG+CMSY10 Type 1 Builtin yes yes yes 292 0 EJNNLN+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 341 0 EJNNJM+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 342 0 EJNNLM+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 343 0 QDCWHF+EURM10 Type 1 Builtin yes yes yes 420 0 NPWAER+EURM7 Type 1 Builtin yes yes yes 475 0 EJNNLN+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 556 0 EJNNJM+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 557 0 EJNNLM+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 558 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-09-10 04:10:51 CEST RepresentationInformation: 335908.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-09-09 13:35:34 CEST Size: 1697605 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 880 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Single-Nucleotide Polymorphisms Affecting Atrial Electrical Activity Children: Item: Title: Genome-Wide Association Studies Item: Title: Impact of Risk SNPs on PITX2 Expression or Function Item: Title: Impact of Risk SNPs on Cardiomyocyte Function Item: Title: Impact of Risk SNPs on Atrial Function Item: Title: Impact of Risk SNPs on AF Therapy Item: Title: Modulation of Electrical Activity by PITX2 Children: Item: Title: Relationship Between PITX2 and AF Item: Title: PITX2 Point Mutations and Non-Coding RNA Item: Title: Genetic Manipulation of PITX2 and Experimental Models of Pitx2 Deficiency Children: Item: Title: Mouse Models Item: Title: Zebrafish Model Item: Title: Human Induced Pluripotent Stem Cell (hiPSC) Model Item: Title: HL-1 Model Item: Title: Computational Models Item: Title: Relationship Between PITX2 and AF Therapy Item: Title: Cross-Talk Between PITX2 Signaling, Risk SNPs and Other Transcription Factors Children: Item: Title: PITX2 and 4q25 Item: Title: PITX2 and Other Transcription Factors Item: Title: Pitx2 and Other SNPs Item: Title: Future Directions and Limitations Item: Title: References Info: Title: Single-Nucleotide Polymorphisms, PITX2 and Abnormal Electrical Activity in Atrial Fibrillation Author: Verónica Jiménez-Sábado and Leif Hove-Madsen Subject: Since single-nucleotide polymorphisms (SNPs) associated with increased risk of atrial fibrillation (AF) on chromosome 4q25 are located near the transcription factor PITX2, research has investigated relationships between SNPs, PITX2 activity and atrial function to improve risk stratification and identify new therapies. Although PITX2 levels are heterogeneous, most studies converge towards lower PITX2 levels in patients with AF, and a 4q25 SNP has been reported to reduce PITX2 expression. However, there are several SNPs at 4q25 that segregate independently, and patients carrying different SNPs respond differently to ablation therapy. On the other hand, atrial-specific deletion of Pitx2c mimics molecular and electrophysiological alterations observed in patients with AF. This includes microRNAs, signaling pathways, ion channels, calcium homeostasis, electrical remodeling, contraction and the response to pharmacological treatments. Moreover, mutations in the PITX2 homeodomain are associated with AF, PITX2 dysfunction or impaired calcium homeostasis. Interestingly, myocytes with the 4q25 risk allele rs13143308T display electrophysiological alterations similar to those reported in patients with AF or mice with heterozygous Pitx2c deletion. Moreover, carriers of rs13143308T respond poorly to ablation or antiarrhythmic drug therapy. Future research needs to establish how different 4q25 SNPs impact different PITX2 isoforms and the downstream regulation of atrial function. 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