Cytomegalovirus latency exacerbates cardiac inflammation and tissue remodeling after myocardial infarction

Background: Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, with immune-mediated processes increasingly recognized as important contributors to CVD onset and progression. Seropositivity rates indicate 60–90% of the population carries latent viral infections, e.g., with cytomegalovirus, that profoundly shape the individual immune phenotype. Epidemiological studies have consistently associated cytomegalovirus (CMV) seropositivity with adverse cardiovascular outcomes, yet the functional consequences of latent CVM cytomegalovirus latency in the context of myocardial infarction (MI) have not been studied, nor has its underlying influence on cardiac tissue. Methods: In this study we employed a murine model of cytomegalovirus (MCMV) infection to investigate the impact of the virus in the cardiac immune environment. We characterized the immune cell populations involved in cardiac immune responses by flow cytometry and performed bulk RNA seq of infected and naive mice to dissect the transcriptional differences that occur after viral exposure. To better understand how viral infections affect the myocardium of infected and naive animals post MI, we conducted a series of experiments involving flow cytometry, single-cell RNA / TCR sequencing, echocardiography, and cMRI 5 days after mice underwent experimental MI. Additionally, we used cMRI to stratify CMV- seropositive patients as “good” or “poor healers” and tested their CMV IgG titers. Using TCR-sequencing, we also identified CMV-responding TCRs and compared blood-derived and heart-derived T cells from post-mortem tissues. Results: Our findings show that exposure to murine CMV induces both long-term changes in the cardiac transcriptional profile and alterations in cardiac immune cell populations. We detected the establishment of virus-specific resident memory T cells that persist in cardiac tissue. Following myocardial infarction (MI), mice previously exposed to MCMV had more abundant cardiac-resident T cells, heightened inflammatory profile, and adverse ventricular remodeling, as revealed by MRI, compared to naive controls. These murine observations were supported by data from CMV-seropositive MI patients, who harbored CMV-responsive T cells and exhibited impaired cardiac healing. Conclusions: Taken together, our findings demonstrate that latent CMV infection leads to long-term immunological changes in cardiac tissue that exert significant effects on post-MI healing outcome.