Increased circulating IgG levels, myocardial immune cells and IgG deposits support a role for an immune response in pre‐ and end‐stage heart failure

Abstract

The chronic inflammatory response plays an important role in adverse cardiac remodelling and the development of heart failure (HF). There is also evidence that in the pathogenesis of several cardiovascular diseases, chronic inflammation is accompanied by antibody and complement deposits in the heart, suggestive of a true autoimmune response. However, the role of antibody‐mediated immune responses in HF progression is less clear. We assessed whether immune cell infiltration and immunoglobulin levels are associated with HF type and disease stage, taking sex differences into account. We found IgG deposits and increased infiltration of immune cells in the affected myocardium of patients with end‐stage HF with reduced ejection fraction (HFrEF, n = 20). Circulating levels of IgG1 and IgG3 were elevated in these patients. Furthermore, the percentage of transitional/regulatory B cells was decreased (from 6.9% to 2.4%) compared with healthy controls (n = 5). Similarly, increased levels of circulating IgG1 and IgG3 were observed in men with left ventricular diastolic dysfunction (LVDD, n = 5), possibly an early stage of HF with preserved EF (HFpEF). In conclusion, IgG deposits and infiltrates of immune cells are present in end‐stage HFrEF. In addition, both LVDD patients and end‐stage HFrEF patients show elevated levels of circulating IgG1 and IgG3, suggesting an antibody‐mediated immune response upon cardiac remodelling, which in the early phase of remodelling appear to differ between men and women. These immunoglobulin subclasses might be used as marker for pre‐stage HF and its progression. Future identification of auto‐antigens might open possibilities for new therapeutic interventions.

The role of B cells in heart failure and implications for future immunomodulatory treatment strategies

“…Remarkably, the presence of IgG3 and C3c in the myocardium correlated significantly with the length and severity of illness 4,6 . The evidence provided by this large cohort and others demonstrates a strong association of failing myocardium with B‐cell activation and potentially B cell‐mediated injury in HF in humans 4,6,7 . An experimental model of ischaemic cardiac injury further supports the role of cardiac autoantibodies 8 .…”

“…As the IgG3 subclass exhibit the most effective complement‐fixating activity, 5 its presence in heart tissue can provide powerful signals of cell injury and to recruit inflammatory cells. Remarkably, the presence of IgG3 and C3c in the myocardium correlated significantly with the length and severity of illness 4,6 . The evidence provided by this large cohort and others demonstrates a strong association of failing myocardium with B‐cell activation and potentially B cell‐mediated injury in HF in humans 4,6,7 .…”

“…Th1 response facilitates the activation of B cells 60,61 . IFN‐γ induces IgG3 expression, 62 which is consistent with IgG3 deposits in failing myocardium 4,6 . Finally, IgG3 deposits in patients failing heart tissue are accompanied by mixed inflammatory infiltrates of B cells, T cells, and macrophages 6 …”

“…have recently reported that patients with HF had increased proportions of circulating plasmablasts and decreased transitional/regulatory B cells compared with healthy controls. Interestingly, stratified analysis revealed that these differences were more pronounced in patients with ischaemic HF, which likely reflects the nature of the insult to the myocardium 6 …”

Cardiovascular prognosis: a new role for ceramides and other cardiometabolites

“…However, this requires further confirmation by a larger cohort of patients, preferentially between the patients with comparable levels of PTX3 and NT‐proBNP. Chronic HF is associated with elevated inflammatory state, especially in patients at advanced stages of the disease 23,24 . Considering that levels of PTX3 and NT‐proBNP as well as ceramides are regulated by specific immune responses, 25–27 elevated levels of these three markers in patients with HF who later died of cardiovascular disease may arise from enhanced inflammation.…”