Inflammation in Heart Failure: Is our immune response failing our heart?

Abstract

Heart failure (HF) is one of the most common cardiovascular diseases, affecting approximately 26 million people worldwide and is characterized by adverse cardiac remodeling and a reduced ability of the heart to maintain cardiac output. One of the key players in the chronic setting of adverse cardiac remodeling is the inflammatory response. Inflammation is essential for the activation of reparative pathways after cardiac damage. However, increasing evidence supports a role for an autoimmune response in HF, which is directed against the myocardium itself after initial cardiac damage, and might even accelerate disease progression. In this thesis, we aimed to explore the role of antibody-mediated immune responses in different etiologies and stages of HF, and to extend the conceptual basis for novel therapeutic interventions.

We found increased levels of circulating and bound immunoglobulins and higher levels of inflammatory cells in the myocardium of patients with pre and end-stage HF. We also evaluated the contribution of antibody-mediated immune responses in patients with a genetic cardiomyopathy, caused by a mutation in the phospholamban (PLN) gene. In line with other HF etiologies, we found increased numbers of myocardial immune cells, IgG deposits, complement activation, and circulating immunoglobulins in PLN patients. To get more insight into potential targets of this immune response, we performed an epitope discovery screen, including 26,000 linear epitopes from cardiovascular proteins. We demonstrated that PLN patients show high levels of antibodies against cell-adhesion proteins and structural components of cardiomyocytes, which could be of great importance in the pathogenesis of arrhythmias and HF. Currently, the only treatment option for end-stage HF is cardiac transplantation (HTx), however, even after HTx, inflammation is limiting survival of patients. We hypothesized that a pro-inflammatory state of the end-stage HF recipient prior to HTx might actively contribute to cardiac allograft vasculopathy (CAV) and graft failure. We discovered a significant correlation between pre-HTx immunoglobulin levels and survival time post-HTx. Moreover, we found an association between increased antibody titers pre-HTx and an inflammatory CAV phenotype, which suggests that an activated immune system pre-HTx also influences inflammation in the CAV lesion and thereby initiates a more rapid development of these lesions. Lastly, we demonstrated the in vitro potency of progenitor cells to possibly dampen antibody-mediated immune responses in HF. We demonstrated immunosuppressive actions of mesenchymal stromal cells (MSC) and cardiomyocyte progenitor cells (CPC) on lymphocyte proliferation and antibody secretion, with the strongest effects observed when using MSC. Moreover, we showed that CPC and especially MSC were able to suppress antibody secretion by HF patient-derived cells.

In conclusion, this thesis underscored the potential roles of antibody-mediated immune responses in different etiologies and stages of HF and highlighted some future directions. It is clear that chronic inflammation is failing our heart even more after initial cardiac damage and might therefore be an essential target in the treatment of HF. The next step is to use identified cardiac-specific epitopes to our advantage as diagnostic screening tool to not only monitor HF progression in patients, but also to create new patient-specific immunosuppressive therapies.