Changes in peripheral blood leukocyte composition precede development of heart-reactive autoantibodies in patients hospitalised for acute heart failure

In a retrospective pilot study, we showed that the induction of heart-reactive autoantibodies (HRA) in the wake of acutely decompensated heart failure predicts worse outcomes. To gain deeper insights into the immunological mechanisms causing induction of HRA after heart failure decompensation we initiated the prospective Acute Heart Failure-Immunomonitoring Cohort Study (AHF-ImmunoCS). For this study, 380 patients were enrolled and will be followed up, including serial collection of biomaterials, for a period of 18 months after the index hospitalisation for AHF. Analysis of AHF-ImmunoCS samples obtained at baseline and at 6-month follow-up from 110 patients showed de novo induction of HRA - as detected by indirect immunofluorescence (IFT) - in 21% of patients (previously published percentage: 32%). The IFT results did not reflect induction of broad anti-heart autoimmunity as autoantibodies against other cardiac antigens like Troponin I3 or Myosin Light Chain 7 were not induced in parallel. To understand what drives HRA induction in these patients we longitudinally immunophenotyped peripheral blood leukocytes at baseline, 6-week and 6-month follow-up by high-resolution spectral flow cytometry. Among lymphocytes, induction of HRA in the wake of acute decompensation of heart failure was associated with a higher proportion of CD4+ T cells among lymphocytes, more CD45RA+ CCR7+ naive conventional, i.e. non-regulatory, and more CXCR3+ CCR4- Th1 cells among CD4+ T cells at baseline. Among myeloid cells, there were no differences at baseline between patients going on to develop HRA and those that did not. However, patients developing HRA had higher proportions of eosinophils (six-month follow-up) and lower proportions of Arginase+ HLA-DR- polymorphnuclear myeloid-derived suppressor cells among myeloid cells (six-week and six-month follow-up). Our data, thus, implicate that alterations in the composition of both the lymphoid and the myeloid compartments might drive HRA induction which impacts disease progression and prognosis in AHF.