| First Author | Keppner L | Year | 2018 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 315 |
| Issue | 5 | Pages | H1358-H1367 |
| PubMed ID | 30095974 | Mgi Jnum | J:272453 |
| Mgi Id | MGI:6280146 | Doi | 10.1152/ajpheart.00144.2018 |
| Citation | Keppner L, et al. (2018) Antibodies aggravate the development of ischemic heart failure. Am J Physiol Heart Circ Physiol 315(5):H1358-H1367 |
| abstractText | 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 in agammaglobulinemic mice (AID(-/-)muS(-/-)). Although these animals can produce functional B cells, they cannot synthesize secretory IgM (muS(-/-)) or perform Ig 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 with wild-type infarcted control mice, AID(-/-)muS(-/-) mice exhibited improved cardiac function and reduced remodeling on day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AID(-/-)muS(-/-) mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as matrix metalloproteinase-9, collagen type I a1, collagen type III a1, and IL-6. An unbiased screening of the heart reactivity potential in the plasma of wild-type 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 Fcgamma receptors (CD16/32), suggesting the existence of an in situ IgG-Fcgamma receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic heart failure progression and provide novel insights into the mechanisms underlying this phenomenon. NEW & NOTEWORTHY Our study sheds some light on the long-standing debate over the relevance of autoantibodies in heart failure and might stimulate future research in the field. The observation of extracellular matrix-specific antibodies and the detection of Fcgamma receptor-expressing cells within the scar provide novel insights into the mechanisms by which antibodies may contribute to adverse remodeling. |
