Full Expression of Cardiomyopathy Is Partly Dependent on B-Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis.

BACKGROUND: Limited information exists on the role of B-cell-dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B-cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP). METHODS AND RESULTS: CMP protocol involved the use of l-NAME and NaCl in the drinking water and angiotensin-II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild-type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T- and B-cell deficient); CD22(-) CMP (B-cell depleted); and Nude CMP (T-cell deficient), with their respective controls. We performed B-cell depletion and reconstitution protocols. The protective effect of B-cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22(-) CMP group compared to WT CMP. Once SCID mice underwent B-cell reconstitution with isolated CMP B-cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B-cells stimulate collagen production by cardiac fibroblasts. CONCLUSIONS: The absence of B-cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B-cells play a contributory role in an angiotensin-II-induced HF model.

Therapeutic plasma exchange a potential strategy for patients with advanced heart failure.

BACKGROUND: Previous reports had emphasized the importance of humoral immunity in heart failure in humans, primarily determined by the presence of circulating antibodies. However, there is little or no information about the frequency of anticardiac antibodies present in failing human myocardium. METHODS: Clinical data and myocardial tissue samples were analyzed to determine the role of humoral immunity in patients with chronic heart failure (CHF) in different SETTINGS. RESULTS: Anticardiac antibodies were found present in failing hearts but not in normal control hearts. Further, the level of expression of these anticardiac antibodies changed with the severity of the disease state; and in patients with acute heart failure, we found selective activation of B cells. Finally, treatment of CHF patients with therapeutic plasma exchange, a strategy that removes circulating antibodies, resulted in a reduction in anticardiac antibody deposition and improvements in cardiac function. CONCLUSION: These data collectively suggest a role of humoral immunity in the progression of heart failure.

Evidence for activation of immune system in heart failure: is there a role for anti-inflammatory therapy?

PURPOSE OF REVIEW: The efficacy of already established heart failure therapeutics limits new developments; however, there are still fertile grounds for growth with a better understanding of often overlooked mechanisms of disease. We will review evidence on inflammation and components of the inflammatory process occurring in patients with chronic heart failure, review different therapeutic techniques such as intravenous immunoglobin, plasmapheresis and immuno-adsorption. RECENT FINDINGS: The use of highly specific anti-inflammatory therapeutic strategies in large randomized trials such as anti-TNF-alpha has failed to show clinical benefits; however, by taking a broad spectrum anti-inflammatory approach, strategies as in the ACCLAIM trial have been effective in improving the outcome in a select group of patients. SUMMARY: There is substantial evidence of immune modulation promoting the downregulation of inflammatory cytokines thus increasing several important and potentially therapeutic anti-inflammatory cytokines. It will be necessary to design large multicenter trials to overcome the expected improvements of current therapies, which may overshadow results, and to finally elucidate the therapeutic contributions of immune modulation in heart failure.