Immune Aspects of the Pathogenesis of Dilated Cardiomyopathy
Keywords:
Dilated cardiomyopathy, autoimmunity, viral myocarditis, immunotherapy, precision medicine.Abstract
Dilated cardiomyopathy (DCM) is a progressive myocardial disorder of multifactorial origin, marked by ventricular di-latation and impaired systolic function. While genetic mutations in sarcomeric and cytoskeletal proteins underlie a subset of familial DCM, increasing evidence implicates immune-mediated mechanisms-often triggered by viral myocarditis, molecular mimicry, and persistent autoimmunity-in both idiopathic and post-infectious forms. This review synthesizes recent insights into the innate and adaptive immune responses that drive chronic myocardial inflammation and remodel-ing in DCM. Pattern recognition receptors (e.g., TLRs), proinflammatory cytokines (e.g., TNF-α, IL-6), and autoreactive T and B cells contribute to progressive cardiomyocyte damage. Autoantibodies against β₁-adrenergic and muscarinic re-ceptors further perpetuate dysfunction. Endomyocardial biopsies, cytokine profiling, and next-generation sequencing are instrumental for immunophenotyping and identifying genetic/epigenetic predispositions. We discuss the application of immunosuppressants, IVIG, cytokine blockers, and immunoadsorption, alongside the promise of stratified medicine. Sin-gle-cell transcriptomics and flow cytometry now enable patient-specific treatment targeting pathways such as Th17 po-larization, B-cell activation, or cytokine dysregulation. Moreover, the integration of epigenetic biomarkers-DNA methyl-ation, histone modifications, and miRNAs-offers predictive and therapeutic insights. In conclusion, DCM exemplifies the intersection of immunology and cardiology, where precision immunotherapy tailored to individual immune profiles may enhance therapeutic efficacy, reduce adverse outcomes, and redefine disease management paradigms.
References
Mahmaljy, H., Yelamanchili, V. S., & Singhal, M. (2023, April 7). Dilated cardiomyopathy. In StatPearls. StatPearls Publishing.
Schultheiss, H. P., Fairweather, D., Caforio, A. L. P., Escher, F., Hershberger, R. E., Lipshultz, S. E., et al. (2019). Dilated cardiomyopathy. Nature Reviews Disease Primers, 5(1), 32. https://doi.org/10.1038/s41572-019-0084-1
Brownrigg, J. R., Leo, V., Rose, J., et al. (2021). Epidemiology of cardiomyopathies and incident heart failure in a population-based cohort study. Heart. https://doi.org/10.1136/heartjnl-2020-318226
Codd, M. B., Sugrue, D. D., Gersh, B. J., & Melton, L. J. (1989). Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation, 80(3), 564–572. https://doi.org/10.1161/01.CIR.80.3.564
Hershberger, R. E., Hedges, D. J., & Morales, A. (2013). Dilated cardiomyopathy: The complexity of a diverse genetic architecture. Nature Reviews Cardiology, 10(9), 531–547. https://doi.org/10.1038/nrcardio.2013.105
Wang, E., Zhou, R., Li, T., Hua, Y., Zhou, K., Li, Y., et al. (2023). The molecular role of immune cells in dilated cardiomyopathy. Medicina (Kaunas), 59(7), 1246. https://doi.org/10.3390/medicina59071246
Caforio, A. L., Keeling, P. J., Zachara, E., Mestroni, L., Camerini, F., Mann, J. M., et al. (1994). Evidence from family studies for autoimmunity in dilated cardiomyopathy. The Lancet, 344(8925), 773–777. https://doi.org/10.1016/S0140-6736(94)92340-7
Sozzi, F. B., Gherbesi, E., Faggiano, A., Gnan, E., Maruccio, A., Schiavone, M., et al. (2022). Viral myocarditis: Classification, diagnosis, and clinical implications. Frontiers in Cardiovascular Medicine, 9, 908663. https://doi.org/10.3389/fcvm.2022.908663
Gebhard, J. R., Perry, C. M., Harkins, S., Lane, T., Mena, I., Asensio, V. C., et al. (1998). Coxsackievirus B3-induced myocarditis: Perforin exacerbates disease, but plays no detectable role in virus clearance. American Journal of Pathology, 153(2), 417–428. https://doi.org/10.1016/S0002-9440(10)65585-5
Verdonschot, J., Hazebroek, M., Merken, J., Debing, Y., Dennert, R., Brunner-La Rocca, H. P., et al. (2016). Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: Review of the literature. European Journal of Heart Failure, 18(12), 1430–1441. https://doi.org/10.1002/ejhf.665
Reddy, S., Eliassen, E., Krueger, G. R., & Das, B. B. (2017). Human herpesvirus 6-induced inflammatory cardiomyopathy in immunocompetent children. Annals of Pediatric Cardiology, 10(3), 259–268. https://doi.org/10.4103/apc.APC_49_17
Krych, S., Jęczmyk, A., Jurkiewicz, M., Żurek, M., Jekiełek, M., Kowalczyk, P., et al. (2024). Viral myocarditis as a factor leading to the development of heart failure symptoms, including the role of parvovirus B19 infection—Systematic review. International Journal of Molecular Sciences, 25(15), 8127. https://doi.org/10.3390/ijms25158127
Orphanou, N., Papatheodorou, E., & Anastasakis, A. (2022). Dilated cardiomyopathy in the era of precision medicine: Latest concepts and developments. Heart Failure Reviews, 27(4), 1173–1191. https://doi.org/10.1007/s10741-021-10184-6
Gkouziouta, G., Karavolias, J., Fekos, A., Katsianis, P., Kourkoveli, P. H., Cokkinos, S., et al. (2013). High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. European Heart Journal, 34(suppl_1), P3861. https://doi.org/10.1093/eurheartj/eht308.P3861
Cusick, M. F., Libbey, J. E., & Fujinami, R. S. (2012). Molecular mimicry as a mechanism of autoimmune disease. Clinical Reviews in Allergy & Immunology, 42(1), 102–111. https://doi.org/10.1007/s12016-011-8294-7
Sundaresan, B., Shirafkan, F., Ripperger, K., & Rattay, K. (2023). The role of viral infections in the onset of autoimmune diseases. Viruses, 15(3), 782. https://doi.org/10.3390/v15030782
Shim, S. H., Kim, D. S., Cho, W., & Nam, J. H. (2014). Coxsackievirus B3 regulates T-cell infiltration into the heart by lymphocyte function-associated antigen-1 activation via the cAMP/Rap1 axis. Journal of General Virology, 95(9), 2010–2018. https://doi.org/10.1099/vir.0.065318-0
Kishore, J., & Kishore, D. (2018). Clinical impact and pathogenic mechanisms of human parvovirus B19: A multiorgan disease inflictor incognito. Indian Journal of Medical Research, 148(4), 373–384. https://doi.org/10.4103/ijmr.IJMR_1239_18
Yanagawa, B., Spiller, O. B., Choy, J., Luo, H., Cheung, P., Zhang, H. M., et al. (2003). Coxsackievirus B3-associated myocardial pathology and viral load reduced by recombinant soluble human decay-accelerating factor in mice. Laboratory Investigation, 83(1), 75–85. https://doi.org/10.1097/01.LAB.0000043276.67241.09
Jahns, R., Boivin, V., Hein, L., Triebel, S., Angermann, C. E., Ertl, G., et al. (2004). Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. Journal of Clinical Investigation, 113(10), 1419–1429. https://doi.org/10.1172/JCI20149
Patel, P. A., & Hernandez, A. F. (2013). Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy. European Journal of Heart Failure, 15(7), 724–729. https://doi.org/10.1093/eurjhf/hft060
Zhang, J., Xu, H., Li, Z., Feng, F., Wang, S., & Li, Y. (2025). Frequency of autoantibodies and their associated clinical characteristics and outcomes in patients with dilated cardiomyopathy: A systematic review and meta-analysis. Autoimmunity Reviews, 24(4), 103755. https://doi.org/10.1016/j.autrev.2025.103755
Hu, C., Wong, F. S., & Wen, L. (2009). B cell-directed therapy for autoimmune diseases. Clinical and Experimental Immunology, 157(2), 181–190. https://doi.org/10.1111/j.1365-2249.2009.03962.x
Nindl, V., Maier, R., Ratering, D., De Giuli, R., Züst, R., Thiel, V., et al. (2012). Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. European Journal of Immunology, 42(9), 2311–2321. https://doi.org/10.1002/eji.201142198
Janeway, C. A., Jr., Travers, P., Walport, M., & Shlomchik, M. J. (2001). Immunobiology: The immune system in health and disease (5th ed.). Garland Science.
Liang, K. P., Kremers, H. M., Crowson, C. S., Snyder, M. R., Therneau, T. M., Roger, V. L., et al. (2009). Autoantibodies and the risk of cardiovascular events. Journal of Rheumatology, 36(11), 2462–2469. https://doi.org/10.3899/jrheum.090356
Aristizábal, B., & González, Á. (2013). Innate immune system. In J. M. Anaya, Y. Shoenfeld, & A. Rojas-Villarraga (Eds.), Autoimmunity: From bench to bedside. El Rosario University Press.
Goulopoulou, S., McCarthy, C. G., & Webb, R. C. (2016). Toll-like receptors in the vascular system: Sensing the dangers within. Pharmacological Reviews, 68(1), 142–167. https://doi.org/10.1124/pr.114.010090
Frantz, S., Falcao-Pires, I., Balligand, J. L., Bauersachs, J., Brutsaert, D., Ciccarelli, M., et al. (2018). The innate immune system in chronic cardiomyopathy: A European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC. European Journal of Heart Failure, 20(3), 445–459. https://doi.org/10.1002/ejhf.1138
Högye, M., Mándi, Y., Csanády, M., Sepp, R., & Buzás, K. (2004). Comparison of circulating levels of interleukin-6 and tumor necrosis factor-alpha in hypertrophic cardiomyopathy and in idiopathic dilated cardiomyopathy. American Journal of Cardiology, 94(2), 249–251. https://doi.org/10.1016/j.amjcard.2004.03.069
Frangogiannis, N. G. (2019). The extracellular matrix in ischemic and nonischemic heart failure. Circulation Research, 125(1), 117–146. https://doi.org/10.1161/CIRCRESAHA.119.311148
Coffman, J. A. (2025). Enteroviruses activate cellular innate immune responses prior to adaptive immunity and tropism contributes to severe viral pathogenesis. Microorganisms, 13(4), 870. https://doi.org/10.3390/microorganisms13040870
Jain, P., Jain, A., Khan, D. N., & Kumar, M. (2013). Human parvovirus B19 associated dilated cardiomyopathy. BMJ Case Reports, 2013, bcr2013010410. https://doi.org/10.1136/bcr-2013-010410
Xu, S., Wu, Z., & Chen, H. (2024). Construction and evaluation of immune-related diagnostic model in patients with heart failure caused by idiopathic dilated cardiomyopathy. BMC Cardiovascular Disorders, 24, 92. https://doi.org/10.1186/s12872-024-03862-5
Perugino, C. A., Kaneko, N., Maehara, T., Mattoo, H., Kers, J., Allard-Chamard, H., et al. (2021). CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease. Journal of Allergy and Clinical Immunology, 147(1), 368–382. https://doi.org/10.1016/j.jaci.2020.06.019
Dandel, M. (2025). Autoimmunity in cardiomyopathy-induced heart failure and cardiac autoantibody removal by immunoadsorption. Journal of Clinical Medicine, 14(3), 947. https://doi.org/10.3390/jcm14030947
Bermea, K., Bhalodia, A., Huff, A., Rousseau, S., & Adamo, L. (2022). The role of B cells in cardiomyopathy and heart failure. Current Cardiology Reports, 24(8), 935–946. https://doi.org/10.1007/s11886-022-01722-w
Yoshikawa, T., Baba, A., & Nagatomo, Y. (2009). Autoimmune mechanisms underlying dilated cardiomyopathy. Circulation Journal, 73(4), 602–607. https://doi.org/10.1253/circj.CJ-08-1183
Zhang, L., Hu, D., Li, J., Wu, Y., Liu, X., & Yang, X. (2002). Autoantibodies against the myocardial beta1-adrenergic and M2-muscarinic receptors in patients with congestive heart failure. Chinese Medical Journal (Engl), 115(8), 1127–1131.
Saleh, D., Jones, R. T. L., Schroth, S. L., Thorp, E. B., & Feinstein, M. J. (2023). Emerging roles for dendritic cells in heart failure. Biomolecules, 13(10), 1535. https://doi.org/10.3390/biom13101535
Satoh, M., Nakamura, M., Saitoh, H., Satoh, H., Maesawa, C., Segawa, I., et al. (1999). Tumor necrosis factor-alpha-converting enzyme and tumor necrosis factor-alpha in human dilated cardiomyopathy. Circulation, 99(25), 3260–3265. https://doi.org/10.1161/01.CIR.99.25.3260
Li, H., & Bian, Y. (2024). Fibroblast-derived interleukin-6 exacerbates adverse cardiac remodeling after myocardial infarction. Korean Journal of Physiology & Pharmacology, 28(3), 285–294. https://doi.org/10.4196/kjpp.2024.28.3.285
Pyrillou, K., Burzynski, L. C., & Clarke, M. C. H. (2020). Alternative pathways of IL-1 activation, and its role in health and disease. Frontiers in Immunology, 11, 613170. https://doi.org/10.3389/fimmu.2020.613170
Altara, R., Mallat, Z., Booz, G. W., & Zouein, F. A. (2016). The CXCL10/CXCR3 axis and cardiac inflammation: Implications for immunotherapy to treat infectious and noninfectious diseases of the heart. Journal of Immunology Research, 2016, 4396368. https://doi.org/10.1155/2016/4396368
Nityashree, K. L., Rachitha, P., Hanchinmane, S., & Raghavendra, V. B. (2025). Advancing precision medicine: Uncovering biomarkers and strategies to mitigate immune-related adverse events in immune checkpoint inhibitors therapy. Toxicology Reports, 14, 102035. https://doi.org/10.1016/j.toxrep.2025.102035
Pan, S. Y., Tian, H. M., Zhu, Y., Gu, W. J., Zou, H., Wu, X. Q., et al. (2022). Cardiac damage in autoimmune diseases: Target organ involvement that cannot be ignored. Frontiers in Immunology, 13, 1056400. https://doi.org/10.3389/fimmu.2022.1056400
Bracamonte-Baran, W., & Čiháková, D. (2017). Cardiac autoimmunity: Myocarditis. In Advances in Experimental Medicine and Biology (Vol. 1003, pp. 187–221). https://doi.org/10.1007/978-3-319-57613-8_10
Coutinho, A. E., & Chapman, K. E. (2011). The anti-inflammatory and immunosuppressive effects of glucocorticoids: Recent developments and mechanistic insights. Molecular and Cellular Endocrinology, 335(1), 2–13. https://doi.org/10.1016/j.mce.2010.04.005
Naran, K., Nundalall, T., Chetty, S., & Barth, S. (2018). Principles of immunotherapy: Implications for treatment strategies in cancer and infectious diseases. Frontiers in Microbiology, 9, 3158. https://doi.org/10.3389/fmicb.2018.03158
