Antibodies aggravate the development of ischemic heart failure

Abstract

Heart-specific antibodies have been widely associated with myocardial infarction (MI). However, it remains unclear whether autoantibodies mediate disease progression or are a byproduct of cardiac injury. To disambiguate the role of immunoglobulins in MI, we characterized the development of ischemic heart failure (HF) in agammaglobulinemic mice (AIDμS). While these animals can produce functional B-cells, they cannot synthesize secretory IgM (μS) or perform immunoglobulin class-switching (AID), leading to complete antibody deficiency. Agammaglobulinemia did not affect overall post-MI survival but resulted in a significant reduction in infarct size. Echocardiographic analyses showed that compared to the WT infarcted controls, the AIDμS mice exhibited improved cardiac function and reduced remodeling at day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AIDμS mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as Mmp9, Col1a1, Col3a1, and Il6. An unbiased screening of the heart-reactivity potential in the plasma of WT MI animals revealed the presence of antibodies that target the myocardial scar and collagenase-sensitive epitopes. Moreover, we found that IgG accumulated within the scar tissues of infarcted mice and remained in close proximity with cells expressing Fcγ receptors (CD16/32, FcγR), suggesting the existence of an in situ IgG-Fcγ receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic HF progression and provide novel insights into the mechanisms underlying this phenomenon.

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

“…4,6,7 An experimental model of ischaemic cardiac injury further supports the role of cardiac autoantibodies. 8 In this model, ischaemic injury in control mice produced myocardial infarction (MI) and depressed ejection fraction, while infarct size was reduced, with cardiac function improved in Ig-deficient mice. 8 Autoantibodies might cause injury either by directly interacting with target receptors on heart cells or by triggering signals via their Fc-binding domain when it is interacting with Fc γ-receptors (FcγR) present on the surface of a variety of cells.…”

“…8 In this model, ischaemic injury in control mice produced myocardial infarction (MI) and depressed ejection fraction, while infarct size was reduced, with cardiac function improved in Ig-deficient mice. 8 Autoantibodies might cause injury either by directly interacting with target receptors on heart cells or by triggering signals via their Fc-binding domain when it is interacting with Fc γ-receptors (FcγR) present on the surface of a variety of cells. 9 Activation of FcγR via the antibody Fc-binding domain implies that antibody specificity is irrelevant for this pathway.…”

“…FcγRs are present on cardiac fibroblasts 10 and cardiomyocytes 11 . FcγR signal transduction promotes fibrosis in cardiomyocytes and reduced calcium transients, cell shortening, and induction of cardiac cell death through activation of apoptotic pathways in myocytes 8,10,11 ( Figure ).…”

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

“…In line with this hypothesis, deposits of antibodies (mainly IgG1 and IgG3) in the myocardium of HF patients have been observed. These antibodies, reacting to cardiac tissue, are bound to the failing myocardium where they induce complement activation and most likely play an important role in HF progression . In previous studies, circumstantial evidence has been provided for an antibody‐mediated immune response in end‐stage HF.…”

“…These antibodies, reacting to cardiac tissue, are bound to the failing myocardium where they induce complement activation and most likely play an important role in HF progression. [24][25][26][27][28][29] In previous studies, circumstantial evidence has been provided for an antibody-mediated immune response in end-stage HF. However, the question remains whether this antibody-mediated immune response is associated with the severity of HF.…”