CD69 expression on regulatory T cells protects from immune damage after myocardial infarction.

Increasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69-/- mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Tregs into Cd69-/- mice after LAD ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.

Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis.

Immune checkpoint inhibitors (ICIs) have recently emerged as strong therapies for a broad spectrum of cancers being the first-line treatment for many of them, even improving the prognosis of malignancies that were considered untreatable. This therapy is based on the administration of monoclonal antibodies targeting inhibitory T-cell receptors, which boost the immune system and prevent immune evasion. However, non-specific T-cell de-repression can result in a wide variety of immune-related adverse events (irAEs), including gastrointestinal, endocrine, and dermatologic, with a smaller proportion of these having the potential for fatal outcomes such as neurotoxicity, pulmonary toxicity, and cardiotoxicity. In recent years, alarm has been raised about cardiotoxicity as it has the highest mortality rate when myocarditis develops. However, due to the difficulty in diagnosing this cardiac condition and the lack of clinical guidelines for the management of cardiovascular disease in patients on therapy with ICIs, early detection of myocarditis has become a challenge in these patients. In this review we outline the mechanisms of tolerance by which this fatal cardiomyopathy may develop in selected cancer patients treated with ICIs, summarize preclinical models of the disease that will allow the development of more accurate strategies for its detection and treatment, and discuss the challenges in the future to decrease the risks of its development with better decision making in susceptible patients.

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).