Katelyn Rook

Background: Ischemic heart diseases cause an estimated 17.9 million deaths annually, with most of these cases involving myocardial infarction (MI) of left ventricular (LV) cardiac tissue¹. Following an acute MI, the immune system coordinates an inflammatory response to clear damaged tissue and promote wound healing². As a result of this prolonged response, cardiac tissue can undergo adverse remodeling, leading to cardiac dysfunction, known as ischemic cardiomyopathy². Increasing severity of ischemic cardiomyopathy is associated with larger infarct sizes from an MI. As a result, current treatments are focused on the rapid reperfusion of tissue through options such as thrombolysis or surgical revascularization². Despite tissue reperfusion, the immune system’s inflammatory response still occurs. The early phase inflammatory response involves the recruitment of neutrophils and monocytes to promote inflammation, fibroblast activation, and ECM deposition³. While more is understood about the initial inflammatory response, the fast activation time of these early inflammatory agents makes it difficult to modulate in a clinical setting, however, more research is being conducted to understand T-lymphocytes’ role in the long-term immune response and cardiac remodeling^1,3.

Objective: This narrative review aims to understand how various T-lymphocyte subsets impact cardiac tissue remodeling in the immune response to MI.

Search Methods: Using the PubMed database, an online search was conducted for articles from 2017-2023 using the keywords “T-lymphocytes”, “Cardiac Remodeling”, and “Ischemic Cardiomyopathy”.

Results: The first article showed the initial expansion of T-cells in peripheral blood of mice with surgically induced MI⁴. This study also showed the localization and activation of CD4+ and C8+ T-cells specifically to damaged cardiac tissue, 8 weeks post-MI⁴. Focusing on CD4+ cells, the same authors found that CD4+ depletion in mouse models prevented LV remodeling, while transferring activated CD4+ into naïve mice induced LV dysfunction⁴. Additionally, the manipulation of T-bet, a transcription factor for Th1 cells, a CD4+ subset, was found to limit the extent of cardiac hypertrophy and fibrosis and lower mortality rates in T-bet deficient mice following induced MI⁵. The next study focused on regulatory T-cells, showing them to have a dysfunctional state in the heart failure environment⁶. This included causing antiangiogenic effects by inhibiting circulating angiogenic cell mobilization, which impacted neovascularization and increased cardiac hypertrophy⁶. Regarding CD8+ cells, Granzyme B, the protease within these T-cells, was shown to be released in ischemic cardiac tissues of mice models⁷. A Granzyme B deficiency study showed decreased infarct size and fibrosis and better survival rates following MI⁷. Finally, an immunosuppressive therapy clinical trial found long-term improvements to cardiac function and lower risks for cardiovascular death and need for heart transplant in participating patients with virus-negative inflammatory cardiomyopathy⁸.

Conclusion: Multiple T-lymphocyte subsets impact the inflammatory response and subsequent development of ischemic cardiomyopathy. The current research suggests potential immunomodulatory targets to prevent adverse cardiac remodeling in the post-MI heart. More targeted approaches of immunosuppressive therapy should be explored utilizing the greater understanding of the roles of CD4+, CD8+, and regulatory T-cells in cardiac remodeling.

Works Cited.

1. Bejjani AT, Saab SA, Muhieddine DH, Habeichi NJ, Booz GW, Zouein FA. Spatiotemporal Dynamics of Immune Cells in Early Left Ventricular Remodeling After Acute Myocardial Infarction in Mice. J Cardiovasc Pharmacol. 2020;75(2): 112-122. doi:10.1097/FJC.0000000000000777
2. Del Buono MG, Moroni F, Montone RA, Azzalini L, Sanna T, Abbate A. Ischemic Cardiomyopathy and Heart Failure After Acute Myocardial Infarction. Curr Cardiol Rep. 2022;24(10):1505-1515. doi:10.1007/s11886-022-01766-6
3. Theall B, Alcaide P. The heart under pressure: immune cells in fibrotic remodeling. Curr Opin Physiol. 2022;25:100484. doi:10.1016/j.cophys.2022.100484
4. Bansal SS, Ismahil MA, Goel M, et al. Activated T Lymphocytes are Essential Drivers of Pathological Remodeling in Ischemic Heart Failure. Circ Heart Fail. 2017;10(3):e003688. doi:10.1161/CIRCHEARTFAILURE.116.003688
5. Ma ZG, Dai J, Yuan YP, et al. T-bet deficiency attenuates cardiac remodeling in rats. Basic Res Cardiol. 2018;113(3):19. Published 2018 Mar 21. doi:10.1007/s00395-018-0678-x
6. Bansal SS, Ismahil MA, Goel M, et al. Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy. Circulation. 2019;139(2):206-221. doi:10.1161/CIRCULATIONAHA.118.036065
7. Santos-Zas I, Lemarié J, Zlatanova I, et al. Cytotoxic CD8⁺T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling. Nat Commun. 2021;12(1):1483. Published 2021 Mar 5. doi:10.1038/s41467-021-21737-9
8. Chimenti C, Russo MA, Frustaci A. Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial. Eur Heart J. 2022;43(36):3463-3473. doi:10.1093/eurheartj/ehac348