Autoimmunity and Biological Therapies in Cardiac Arrhythmias
Main Article Content
Abstract
Autoimmune (AI) diseases have a notable rise globally, affecting up to 9.4% of the global population. Cardiac involvement is not unusual in AI diseases, leading to arrhythmias through many pathophysiological mechanisms like myocardial inflammation, fibrosis, and autoantibodies targeting critical cardiac structures, leading to cardiac rhythm disorders. This review focuses on the role of autoantibodies in arrhythmias in diseases like sarcoidosis, lupus, rheumatoid arthritis, scleroderma, and others, highlighting new findings about autoantibodies against critical structural myocardial components. On the other hand, the review describes the AI association with conditions such as sinus bradycardia, atrioventricular blocks, inappropriate sinus tachycardia, atrial fibrillation, ventricular tachycardia, and sudden cardiac death, describing those processes. Emerging biomarkers indicative of inflammation, fibrosis, and autoimmunity that can predict arrhythmia risk are examined. The review also explores the field of managing cardiac arrhythmias with alternative cell therapy approaches that target gene substrate as a promising way to transfer, silence, and edit cellular disorders associated with arrhythmia generation that may help treat these conditions in the future.
Keywords:
Atrial fibrillation, Autoimmune disease, Immunosuppression, Inflammation, Remodeling
Article Details
How to Cite
ADAMS, Christian David.
Autoimmunity and Biological Therapies in Cardiac Arrhythmias.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5476>. Date accessed: 02 july 2024.
doi: https://doi.org/10.18103/mra.v12i6.5476.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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25. Shah, H. H. et al. Cardiac sarcoidosis: a comprehensive review of risk factors, pathogenesis, diagnosis, clinical manifestations, and treatment strategies. Frontiers in Cardiovascular Medicine vol. 10 Preprint at https://doi.org/10.3389/fcvm.2023.1156474 (2023).
26. Giannelou, M. & Mavragani, C. P. Cardiovascular disease in systemic lupus erythematosus: A comprehensive update. Journal of Autoimmunity vol. 82 1–12 Preprint at https://doi.org/10.1016/j.jaut.2017.05.008 (2017).
27. Bourré-Tessier, J. et al. Electrocardiographic findings in systemic lupus erythematosus: Data from an international inception cohort. Arthritis Care Res (Hoboken) 67, 128–135 (2015).
28. Santos-Pardo, I. et al. Anti-Ro/SSA antibodies and cardiac rhythm disturbances: Present and future perspectives. International Journal of Cardiology vol. 184 244–250 Preprint at https://doi.org/10.1016/j.ijcard.2014.11.002 (2015).
29. Akuka, A. et al. Association of anti-Ro seropositivity with cardiac rhythm and conduction disturbances. Eur Heart J 43, 4912–4919 (2022).
30. Myung, G. et al. Prevalence of resting-ECG abnormalities in systemic lupus erythematosus: a single-center experience. Clin Rheumatol 36, 1311–1316 (2017).
31. Engelmann, M. D. M. & Svendsen, J. H. Inflammation in the genesis and perpetuation of atrial fibrillation. European Heart Journal vol. 26 2083–2092 Preprint at https://doi.org/10.1093/eurheartj/ehi350 (2005).
32. Wen, S. N. et al. Catheter ablation of atrial fibrillation in patients with rheumatoid arthritis. J Cardiol 66, 320–325 (2015).
33. Mavrogeni, S. et al. Cardiac magnetic resonance predicts ventricular arrhythmias in scleroderma: The Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS). Rheumatology (United Kingdom) 59, 1938–1948 (2020).
34. Wozniak, J. et al. Evaluation of heart rhythm variability and arrhythmia in children with systemic and localized scleroderma. Journal of Rheumatology 36, 191–196 (2009).
35. Vrancianu, C. A. et al. Arrhythmias and Conduction Disturbances in Patients with Systemic Sclerosis—A Systematic Literature Review. International Journal of Molecular Sciences vol. 23 Preprint at https://doi.org/10.3390/ijms232112963 (2022).
36. Simsek, H. et al. Increased risk of atrial and ventricular arrhythmia in long-lasting psoriasis patients. The Scientific World Journal 2013, (2013).
37. Ungprasert, P., Srivali, N. & Kittanamongkolchai, W. Psoriasis and risk of incident atrial fibrillation: A systematic review and meta-analysis. Indian Journal of Dermatology, Venereology and Leprology vol. 82 489–497 Preprint at https://doi.org/10.4103/0378-6323.186480 (2016).
38. Lu, Z., Guo-Chun, W., Li, M. & Ning, Z. Cardiac involvement in adult polymyositis or dermatomyositis: A systematic review. Clinical Cardiology vol. 35 685–691 Preprint at https://doi.org/10.1002/clc.22026 (2012).
39. Lundberg, I. E. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus vol. 14 708–712 Preprint at https://doi.org/10.1191/0961203305lu2205oa (2005).
40. Miloslavsky, E. & Unizony, S. The Heart in Vasculitis. Rheumatic Disease Clinics of North America vol. 40 11–26 Preprint at https://doi.org/10.1016/j.rdc.2013.10.006 (2014).
41. Jia, G. & Sowers, J. R. Autoantibodies of β-adrenergic and M2 cholinergic receptors: atrial fibrillation in hyperthyroidism. Endocrine vol. 49 301–303 Preprint at https://doi.org/10.1007/s12020-015-0556-3 (2015).
42. Reddy, V., Taha, W., Kundumadam, S. & Khan, M. Atrial fibrillation and hyperthyroidism: A literature review. Indian Heart Journal vol. 69 545–550 Preprint at https://doi.org/10.1016/j.ihj.2017.07.004 (2017).
43. Kristensen, S. L. et al. Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: A nationwide study. Europace 16, 477–484 (2014).
44. Qu, Y. S. et al. Autoimmune Calcium Channelopathies and Cardiac Electrical Abnormalities. Frontiers in Cardiovascular Medicine vol. 6 Preprint at https://doi.org/10.3389/fcvm.2019.00054 (2019).
45. Chua, W. et al. Data-driven discovery and validation of circulating blood-based biomarkers associated with prevalent atrial fibrillation. Eur Heart J 40, 1268–1276 (2019).
46. Adlan, A. M., Panoulas, V. F., Smith, J. P., Fisher, J. P. & Kitas, G. D. Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis. Journal of Rheumatology 42, 421–428 (2015).
47. Lin, Y. N., Miguel-dos-Santos, R. & Cingolani, E. Biological Modification of Arrhythmogenic Substrates by Cell-Free Therapeutics. Heart Lung Circ 32, 844–851 (2023).
48. Pérez, P. R., Hylind, R. J., Roston, T. M., Bezzerides, V. J. & Abrams, D. J. Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia. Heart Lung Circ 32, 790–797 (2023).
49. Mesquita, T., Miguel-Dos-Santos, R. & Cingolani, E. Biological Pacemakers: Present and Future. Circ Res 134, 837–841 (2024).
50. Ryan, T. & Roberts, J. D. Emerging Targeted Therapies for Inherited Cardiomyopathies and Arrhythmias. Cardiac Electrophysiology Clinics vol. 15 261–271 Preprint at https://doi.org/10.1016/j.ccep.2023.04.006 (2023).
51. McRae, C., Kapoor, A., Kanda, P., Hibbert, B. & Davis, D. R. Systematic review of biological therapies for atrial fibrillation. Heart Rhythm 16, 1399–1407 (2019).
52. Yoo, S., Geist, G. E., Pfenniger, A., Rottmann, M. & Arora, R. Recent advances in gene therapy for atrial fibrillation. Journal of Cardiovascular Electrophysiology vol. 32 2854–2864 Preprint at https://doi.org/10.1111/jce.15116 (2021).
53. Su, C.-H., Wu, Y.-J., Wang, H.-H. & Yeh, H.-I. Nonviral gene therapy targeting cardiovascular system. Am J Physiol Heart Circ Physiol 303, 629–638 (2012).
54. Turnbull, I. C. et al. Myocardial delivery of lipidoid nanoparticle carrying modRNA induces rapid and transient expression. Molecular Therapy 24, 66–75 (2016).
55. Kaur, K. & Zangi, L. Modified mRNA as a Therapeutic Tool for the Heart. Cardiovasc Drugs Ther 34, 871–880 (2020).
56. Zhao-Fleming, H. H. et al. Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis. Front Immunol 13, (2022).
57. Greener, I. & Donahue, J. K. Gene therapy strategies for cardiac electrical dysfunction. Journal of Molecular and Cellular Cardiology vol. 50 759–765 Preprint at https://doi.org/10.1016/j.yjmcc.2010.07.022 (2011).
58. Rincon, M. Y., VandenDriessche, T. & Chuah, M. K. Gene therapy for cardiovascular disease: Advances in vector development, targeting, and delivery for clinical translation. Cardiovascular Research vol. 108 4–20 Preprint at https://doi.org/10.1093/cvr/cvv205 (2015).
59. Greenberg, B. et al. Design of a Phase 2b Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Advanced Heart Failure. The CUPID 2 Trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b). JACC Heart Fail 2, 84–92 (2014).
60. Greener, I. D. et al. Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction. J Am Coll Cardiol 60, 1103–1110 (2012).
61. Driessen, H. E., Van Veen, T. A. B. & Boink, G. J. J. Emerging molecular therapies targeting myocardial infarction-related arrhythmias. Europace vol. 19 518–528 Preprint at https://doi.org/10.1093/europace/euw198 (2017).
62. Kapoor, N., Liang, W., Marbán, E. & Cho, H. C. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol 31, 54–62 (2013).
2. Lee, H. C. & Melduni, R. M. Autoimmunity and cardiac arrhythmias in endemic pemphigus foliaceus—Association, correlation, or causation? Heart Rhythm vol. 15 732–733 Preprint at https://doi.org/10.1016/j.hrthm.2018.01.023 (2018).
3. Gawałko, M. et al. Cardiac arrhythmias in autoimmune diseases. Circulation Journal vol. 84 685–694 Preprint at https://doi.org/10.1253/circj.CJ-19-0705 (2020).
4. Lazzerini, P. E., Capecchi, P. L., Laghi-Pasini, F. & Boutjdir, M. Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias. Nature Reviews Cardiology vol. 14 521–535 Preprint at https://doi.org/10.1038/nrcardio.2017.61 (2017).
5. Eisen, A., Arnson, Y., Dovrish, Z., Hadary, R. & Amital, H. Arrhythmias and Conduction Defects in Rheumatological Diseases-A Comprehensive Review. Seminars in Arthritis and Rheumatism vol. 39 145–156 Preprint at https://doi.org/10.1016/j.semarthrit.2008.05.001 (2009).
6. Lee, H. C., Huang, K. T. L., Wang, X. L. & Shen, W. K. Autoantibodies and cardiac arrhythmias. Heart Rhythm 8, 1788–1795 (2011).
7. Lazzerini, P. E. et al. Autoantibody-mediated cardiac arrhythmias: Mechanisms and clinical implications. Basic Research in Cardiology vol. 103 1–11 Preprint at https://doi.org/10.1007/s00395-007-0686-8 (2008).
8. Hernández, C. C. et al. Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas’ disease. Journal of Receptors and Signal Transduction 28, 375–401 (2008).
9. Lazzerini, P. E., Laghi-Pasini, F., Boutjdir, M. & Capecchi, P. L. Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome. Frontiers in Medicine vol. 8 Preprint at https://doi.org/10.3389/fmed.2021.730161 (2021).
10. Schulze, W., Kunze Phd, R. & Wallukat, G. Pathophysiological Role of Autoantibodies against G-Protein-Coupled Receptors in the Cardiovascular System. Exp Clin Cardiol vol. 10 (2005).
11. Lazzerini, P. E. et al. Anti-Ro/SSA Antibodies Blocking Calcium Channels as a Potentially Reversible Cause of Atrioventricular Block in Adults. JACC Clin Electrophysiol 9, 1631–1648 (2023).
12. Plastiras, S. C. & Moutsopoulos, H. M. Arrhythmias and conduction disturbances in autoimmune rheumatic disorders. Arrhythm Electrophysiol Rev 10, 17–25 (2021).
13. Chiale, P. A. et al. Inappropriate sinus tachycardia may be related to an immunologic disorder involving cardiac β andrenergic receptors. Heart Rhythm 3, 1182–1186 (2006).
14. Hammerer-Lercher, A., Namdar, M. & Vuilleumier, N. Emerging biomarkers for cardiac arrhythmias. Clinical Biochemistry vol. 75 1–6 Preprint at https://doi.org/10.1016/j.clinbiochem.2019.11.012 (2020).
15. Maguy, A., Mahendran, Y., Tardif, J. C., Busseuil, D. & Li, J. Autoimmune Atrial Fibrillation. Circulation 148, 487–498 (2023).
16. Boccellino, M. et al. International Journal of Molecular Sciences Review Autoantibodies in Atrial Fibrillation-State of the Art. Int. J. Mol. Sci 2023, 1852 (2023).
17. Maguy, A., Tardif, J. C., Busseuil, D., Ribi, C. & Li, J. Autoantibody Signature in Cardiac Arrest. Circulation 141, 1764–1774 (2020).
18. Capecchi, P. L. et al. Autoimmune and inflammatory K+ channelopathies in cardiac arrhythmias: Clinical evidence and molecular mechanisms. Heart Rhythm 16, 1273–1280 (2019).
19. Cimaz, R. et al. QT INTERVAL PROLONGATION IN ASYMPTOMATIC ANTI-SSA/Ro-POSITIVE INFANTS WITHOUT CONGENITAL HEART BLOCK. Arthritis Rheum 43, 1049–1053 (2000).
20. Lazzerini, P. E., Laghi-Pasini, F., Boutjdir, M. & Capecchi, P. L. Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies. Nature Reviews Immunology vol. 19 63–64 Preprint at https://doi.org/10.1038/s41577-018-0098-z (2019).
21. Lazzerini, P. E. et al. Comparison of Frequency of Complex Ventricular Arrhythmias in Patients With Positive Versus Negative Anti-Ro/SSA and Connective Tissue Disease. American Journal of Cardiology 100, 1029–1034 (2007).
22. Labovsky, V., Smulski, C. R., Gómez, K., Levy, G. & Levin, M. J. Anti-β1-adrenergic receptor autoantibodies in patients with chronic Chagas heart disease. Clin Exp Immunol 148, 440–449 (2007).
23. Baba, A., Yoshikawa, T. & Ogawa, S. Autoantibodies Produced Against Sarcolemmal Na-K-ATPase: Possible Upstream Targets of Arrhythmias and Sudden Death in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol 40, 1153–1162 (2002).
24. Ryabkova, V. A. et al. Lethal immunoglobulins: Autoantibodies and sudden cardiac death. Autoimmunity Reviews vol. 18 415–425 Preprint at https://doi.org/10.1016/j.autrev.2018.12.005 (2019).
25. Shah, H. H. et al. Cardiac sarcoidosis: a comprehensive review of risk factors, pathogenesis, diagnosis, clinical manifestations, and treatment strategies. Frontiers in Cardiovascular Medicine vol. 10 Preprint at https://doi.org/10.3389/fcvm.2023.1156474 (2023).
26. Giannelou, M. & Mavragani, C. P. Cardiovascular disease in systemic lupus erythematosus: A comprehensive update. Journal of Autoimmunity vol. 82 1–12 Preprint at https://doi.org/10.1016/j.jaut.2017.05.008 (2017).
27. Bourré-Tessier, J. et al. Electrocardiographic findings in systemic lupus erythematosus: Data from an international inception cohort. Arthritis Care Res (Hoboken) 67, 128–135 (2015).
28. Santos-Pardo, I. et al. Anti-Ro/SSA antibodies and cardiac rhythm disturbances: Present and future perspectives. International Journal of Cardiology vol. 184 244–250 Preprint at https://doi.org/10.1016/j.ijcard.2014.11.002 (2015).
29. Akuka, A. et al. Association of anti-Ro seropositivity with cardiac rhythm and conduction disturbances. Eur Heart J 43, 4912–4919 (2022).
30. Myung, G. et al. Prevalence of resting-ECG abnormalities in systemic lupus erythematosus: a single-center experience. Clin Rheumatol 36, 1311–1316 (2017).
31. Engelmann, M. D. M. & Svendsen, J. H. Inflammation in the genesis and perpetuation of atrial fibrillation. European Heart Journal vol. 26 2083–2092 Preprint at https://doi.org/10.1093/eurheartj/ehi350 (2005).
32. Wen, S. N. et al. Catheter ablation of atrial fibrillation in patients with rheumatoid arthritis. J Cardiol 66, 320–325 (2015).
33. Mavrogeni, S. et al. Cardiac magnetic resonance predicts ventricular arrhythmias in scleroderma: The Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS). Rheumatology (United Kingdom) 59, 1938–1948 (2020).
34. Wozniak, J. et al. Evaluation of heart rhythm variability and arrhythmia in children with systemic and localized scleroderma. Journal of Rheumatology 36, 191–196 (2009).
35. Vrancianu, C. A. et al. Arrhythmias and Conduction Disturbances in Patients with Systemic Sclerosis—A Systematic Literature Review. International Journal of Molecular Sciences vol. 23 Preprint at https://doi.org/10.3390/ijms232112963 (2022).
36. Simsek, H. et al. Increased risk of atrial and ventricular arrhythmia in long-lasting psoriasis patients. The Scientific World Journal 2013, (2013).
37. Ungprasert, P., Srivali, N. & Kittanamongkolchai, W. Psoriasis and risk of incident atrial fibrillation: A systematic review and meta-analysis. Indian Journal of Dermatology, Venereology and Leprology vol. 82 489–497 Preprint at https://doi.org/10.4103/0378-6323.186480 (2016).
38. Lu, Z., Guo-Chun, W., Li, M. & Ning, Z. Cardiac involvement in adult polymyositis or dermatomyositis: A systematic review. Clinical Cardiology vol. 35 685–691 Preprint at https://doi.org/10.1002/clc.22026 (2012).
39. Lundberg, I. E. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus vol. 14 708–712 Preprint at https://doi.org/10.1191/0961203305lu2205oa (2005).
40. Miloslavsky, E. & Unizony, S. The Heart in Vasculitis. Rheumatic Disease Clinics of North America vol. 40 11–26 Preprint at https://doi.org/10.1016/j.rdc.2013.10.006 (2014).
41. Jia, G. & Sowers, J. R. Autoantibodies of β-adrenergic and M2 cholinergic receptors: atrial fibrillation in hyperthyroidism. Endocrine vol. 49 301–303 Preprint at https://doi.org/10.1007/s12020-015-0556-3 (2015).
42. Reddy, V., Taha, W., Kundumadam, S. & Khan, M. Atrial fibrillation and hyperthyroidism: A literature review. Indian Heart Journal vol. 69 545–550 Preprint at https://doi.org/10.1016/j.ihj.2017.07.004 (2017).
43. Kristensen, S. L. et al. Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: A nationwide study. Europace 16, 477–484 (2014).
44. Qu, Y. S. et al. Autoimmune Calcium Channelopathies and Cardiac Electrical Abnormalities. Frontiers in Cardiovascular Medicine vol. 6 Preprint at https://doi.org/10.3389/fcvm.2019.00054 (2019).
45. Chua, W. et al. Data-driven discovery and validation of circulating blood-based biomarkers associated with prevalent atrial fibrillation. Eur Heart J 40, 1268–1276 (2019).
46. Adlan, A. M., Panoulas, V. F., Smith, J. P., Fisher, J. P. & Kitas, G. D. Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis. Journal of Rheumatology 42, 421–428 (2015).
47. Lin, Y. N., Miguel-dos-Santos, R. & Cingolani, E. Biological Modification of Arrhythmogenic Substrates by Cell-Free Therapeutics. Heart Lung Circ 32, 844–851 (2023).
48. Pérez, P. R., Hylind, R. J., Roston, T. M., Bezzerides, V. J. & Abrams, D. J. Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia. Heart Lung Circ 32, 790–797 (2023).
49. Mesquita, T., Miguel-Dos-Santos, R. & Cingolani, E. Biological Pacemakers: Present and Future. Circ Res 134, 837–841 (2024).
50. Ryan, T. & Roberts, J. D. Emerging Targeted Therapies for Inherited Cardiomyopathies and Arrhythmias. Cardiac Electrophysiology Clinics vol. 15 261–271 Preprint at https://doi.org/10.1016/j.ccep.2023.04.006 (2023).
51. McRae, C., Kapoor, A., Kanda, P., Hibbert, B. & Davis, D. R. Systematic review of biological therapies for atrial fibrillation. Heart Rhythm 16, 1399–1407 (2019).
52. Yoo, S., Geist, G. E., Pfenniger, A., Rottmann, M. & Arora, R. Recent advances in gene therapy for atrial fibrillation. Journal of Cardiovascular Electrophysiology vol. 32 2854–2864 Preprint at https://doi.org/10.1111/jce.15116 (2021).
53. Su, C.-H., Wu, Y.-J., Wang, H.-H. & Yeh, H.-I. Nonviral gene therapy targeting cardiovascular system. Am J Physiol Heart Circ Physiol 303, 629–638 (2012).
54. Turnbull, I. C. et al. Myocardial delivery of lipidoid nanoparticle carrying modRNA induces rapid and transient expression. Molecular Therapy 24, 66–75 (2016).
55. Kaur, K. & Zangi, L. Modified mRNA as a Therapeutic Tool for the Heart. Cardiovasc Drugs Ther 34, 871–880 (2020).
56. Zhao-Fleming, H. H. et al. Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis. Front Immunol 13, (2022).
57. Greener, I. & Donahue, J. K. Gene therapy strategies for cardiac electrical dysfunction. Journal of Molecular and Cellular Cardiology vol. 50 759–765 Preprint at https://doi.org/10.1016/j.yjmcc.2010.07.022 (2011).
58. Rincon, M. Y., VandenDriessche, T. & Chuah, M. K. Gene therapy for cardiovascular disease: Advances in vector development, targeting, and delivery for clinical translation. Cardiovascular Research vol. 108 4–20 Preprint at https://doi.org/10.1093/cvr/cvv205 (2015).
59. Greenberg, B. et al. Design of a Phase 2b Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Advanced Heart Failure. The CUPID 2 Trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b). JACC Heart Fail 2, 84–92 (2014).
60. Greener, I. D. et al. Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction. J Am Coll Cardiol 60, 1103–1110 (2012).
61. Driessen, H. E., Van Veen, T. A. B. & Boink, G. J. J. Emerging molecular therapies targeting myocardial infarction-related arrhythmias. Europace vol. 19 518–528 Preprint at https://doi.org/10.1093/europace/euw198 (2017).
62. Kapoor, N., Liang, W., Marbán, E. & Cho, H. C. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol 31, 54–62 (2013).