Telomere Length Is Associated With Adverse Atrial Remodeling in Patients With Atrial Fibrillation

Figures

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  Figure 1. Representative bipolar voltage maps from patients undergoing catheter ablation. Patients were assigned to 2 groups: no/minor low voltage areas <10% and extensive low voltage areas ≥40%. Red color indicates a low voltage area (<0.1 mV) as a surrogate for fibrosis, purple represents healthy atrial tissue. AP indicates anterior–posterior view; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; MV, mitral valve; PA, posterior–anterior view; RIPV, right inferior pulmonary vein; and RSPV, right superior pulmonary vein.

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  Figure 2. Patients with short telomeres show advanced atrial remodeling. A, Age‐adjusted telomere length (TL) correlates with low voltage area (LVAs). 49.29% of all patients with persistent atrial fibrillation had ΔTel <0 compared with age‐adjusted individuals without atrial fibrillation. 60% of these patients with delta TL<0 had advanced LVAs. Patients could be assigned to 3 groups: stage I (long telomeres−no/low LVAs), stage II (short telomeres−no/low LVAs), stage III (short telomeres−advanced LVAs). B, Patients with shorter telomeres had more prominent LVAs, (P=0.033, Fisher exact test). C, Correlation of epigenetic age to chronological age. n=71–72. D, TL and fibrosis correlates with treatment outcome after catheter ablation. 62.5% of patient in stage I (long telomeres−no/low LVAs) were in stable sinus rhythm 24 months after ablation, whereas 50% of patient in stage II (short telomeres−no/low LVAs) and only 26.5% of patients in stage III (short telomeres−advanced LVAs) were in stable sinus rhythm 24 months after ablation. ΔTel age‐adapted TL.

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  Figure 3. Gene ontology (GO) and gene set enrichment analysis of differentially expressed genes (DEGs) in different subgroups of patients according to telomere length (TL) and fibrosis. A, GO comparison of DEGs of patients in stage III with stage I. B, GO analysis of DEGs of patients in stage III with stage II. The abscissa represents the gene ratio factor, and the ordinate represents the name of the GO terms. The size of each circle represents the number of DEGs enriched in the corresponding process and colors represent the P value. C, GSEA analysis of patients in stage III compared with stage I. D, GSEA analysis comparing patients in stage III vs stage II. n=72. P<0.05 was considered significant. GSEA indicates gene set enrichment analysis; and NES, normalized enrichment score.

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  Figure 4. Clonal hematopoiesis of indeterminate potential in patients according to telomere length. A, The most frequent somatic mutations were found in DNMT3A, TET2, and ASXL1. B, Clonal hematopoiesis of indeterminate potential frequency is higher in patients with atrial fibrillation with short telomeres compared with patients with long telomeres (shown in percentage), Fisher exact test, P=0.577. n=71. CHIP indicates clonal hematopoiesis of indeterminate potential.

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  Figure 5. Left atrial fibrosis in mouse models with shorter telomeres. A, Representative pictures of immunofluorescence staining with antibody against collagen I and Titin and counterstaining with DAPI. B, Quantification of collagen I (fibrosis) in wild‐type (WT) and Tert −/− fourth generation mice, n=5 per group. C, Gene expression of profibrotic and fibrotic markers in left atrium of WT and Tert −/− third generation mice. n=3–4 per group, data are expressed as mean±SEM. *P<0.05. Scale bars=50 μmol. Acta2 indicates Alpha‐smooth muscle Actin; Fn, fibronectin; Ctgf, connective tissue growth factor; and Col1A2, collagen type I alpha 2 chain.

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  Figure 6. Schematic diagram. Telomere shortening and atrial fibrosis—proposed mechanism. Telomeres shorten due to aging, stress or certain mutations. These shortened telomeres lead to an increased activity of myeloid cells or erythrocytes, which in turn induce inflammation with fibroblast to myofibroblast transformation. Myofibroblasts deposit extra cellular matrix resulting in atrial fibrosis. CHIP indicates clonal hematopoiesis of indeterminate potential.