Michael Fu， Sahlgrenska University Hospital， Gothenburg University， Sweden

Although mortality due to heart failure has decreased significantly last decade since the introduction of ACE inhibitors， β-adrenergic receptor blockers and angiotensine II receptor subtype 1 blocker in the management of chronic heart failure (CHF)， chronic heart failure remains to be one of most important causes for morbidity and mortality and has very high frequency for readmission to hospitalization because of aggravation of heart failure， which accounts for a significantly higher health-care expenditure that is more than twice that of the cost for cancer. One of most important reasons is that the present heart failure management is aimed mostly at restoration of neurohormonal balance， rather than targeting primary causes of the disease.

Inflammation in CHF: biomarker or target?

 There is increasing evidence showing that inflammation is involved in the progression of heart failure mostly in younger patients. Up to now CHF has been shown to be accompanied by immune activations with proinflammatory cytokines (e.g. TNF-α， IL-1， IL-6) overexpressed both in the systemic circulation and locally in the failing myocardium. Circulating markers of inflammation， such as TNF-α， IL-6 and C-reactive protein (CRP)， have been used in establishing the diagnosis and gauging prognosis in patients with heart failure in the younger. In addition， inflammatory cytokines have been investigated as targets of heart failure therapy. Although results from clinical trials directed against specific cytokine (such as TNF-α) have thus far been disappointing， multiple studies continue to address the importance and therapeutic potential of remodulating the immune response in heart failure.  Likewise， the role of adiponectin in cardiovascular system seems paradoxical. On one hand， in animal studies， adiponectin administration protects development of systolic dysfunction after myocardial infarction. Adiponectin had antihypertrophic effects on cardiac myocytes， and its deficiency exacerbated CHF. In humans， lower plasma adiponectin levels have been connected with increased risk of cardiovascular events and higher incidence of type 2 diabetes mellitus. On the other hand， established CHF patients with a high adiponectin level had poor prognosis. Whereas the relationship between low adiponectin level and an increased risk of coronary arterial disease (CAD) or myocardial infarction seems to be robust， the role of plasma adiponectin in CHF appears to be more complex. Particularly in the elderly heart failure patients this has been poorly studied.

G-protein coupled cardiac receptor autoantibody as both player and biomarker

For almost 2 decades， the autoimmune hypothesis has been considered a “fairy tale “. Although the causes for idiopathic dilated cardiomyopathy (DCM) remain unclear， interest has centered on three possible mechanisms of damage: familial and genetic factors， viral myocarditis and cytotoxic insults， and immunological abnormalities. During last 10 years there have been many investigations showing distinct autoantibodies or other immune factors in heterogeneous subsets of DCM which have contributed supportive and confounding evidence to hypothesis that multiple autoimmune mechanisms are pathophysiologically involved in DCM. For example， since 10 years back， from our laboratory we have unambiguously shown circulating autoantibodies against cardiac β1-adrenergic receptors and M2 muscarinic receptor in patients with DCM. 

Anti-β1 adrenergic receptor autoantibody is probably best studied. There is increasing evidence showing that this autoantibody is causative to DCM. According to Witebsky’s postulates， as indirect evidence it necessitates identification of the responsible “self-antigen” and induction of a similar disease by use of a corresponding self-antigen directed immune response in an experimental animal model， whereas as direct eviden¬ce， it requires repro¬duc-tion of the disease by transfer of homolo¬gous patho¬genic anti¬bo¬dies or pathogenic autoreactive T-cells from one to another in¬dividual of the same species. Last two decades there are a number of studies demonstrating that β1-adrenergic receptor is not only a potent and responsible autoanti¬gen  but also causative to cardiomyopathy by both passive transfer and active immunization in diverse animal models including rabbits， rats and mice. Recently， clinical follow-up study over more than 10 years demonstrated that presence of stimulating anti–β1-AR autoantibodies is independently associated with an about 3-fold increase in all-cause and cardiovascular mortality in DCM.

Interest in autoimmunity has increased in the area of atrial fibrillation (AF) with or without heart failure.  We have previously found anti-M2-muscarinic acetylcholine receptor autoantibodies in patients with idiopathic DCM.  There is an accumulation of evidence showing that anti-M2 autoantibodies are of pathogenic importance in DCM. We recently studied whether the presence of M2 autoantibodies is also associated with AF that often occurs in DCM. We found that M2 autoantibodies were more frequently present in patients with DCM (40%) than in gender and age-matched healthy subjects (8%) as well as in those with chronic AF without left ventricular dysfunction (24%). In patients with DCM， AF was more common in M2-autoantibody positive (40%) than in M2-autoantibody negative patients (18%). In addition to advanced age and enhanced plasma levels of atrial natriuretic peptide， the presence of the M2-autoantibody was found to be the strongest independent predictor of AF development. These results indicate that anti-M2 autoantibodies may be involved in both idiopathic AF and AF in DCM.

Underlying mechanisms for autoantibody-induced impairment in cardiac structure and function

There are many players in the cascade from antibody induction to myocardial damage and gradually developing into DCM. Our previous studies of β1-AR autoantibodies from DCM patients have shown complement-dependent cardiotoxicity and apoptosis and moreover positive chronotropic effects. Sustain stimulation in chronotropic effect is harmful for both cardiac structure and function. Recently it is reported that antibody –induced impairment of cardiac function may be through Fc(gamma) receptor.  However， underlying mechanism from autoantibody to DCM is still largely unknown， in particular how autoimmunity interacts with inflammation， neurohormonal regulation and extracellular matrix proteins.

Immunoadsorption as emerging therapy in CHF

Immunoadsorptions have been conducted last decade in a number of small scale studies. Recently Staudt et al demonstrated that immunoadsorption in one course is equally effective as repetitions at monthly intervals. Because immunoadsorption is an invasive and expensive therapy， a simplified treatment will significantly improve cost effectiveness.  However the underlying mechanism is only partly understood. Removal of autoantibodies is believed to be an important part of it but certainly not the whole truth. As a matter of fact， we have previously shown that the beneficial hemodynamic effects induced by immunoadsorption are not associated directly with removal of β-1-receptor autoantibodies. However this does not mean that the β-1-receptor autoantibodies are not important， rather than those β-1-receptor autoantibodies is not the key mechanism behind this type non-specific immunoadsorption.  In the nature of autoimmunity， there is often multiantigenicity. The specific immunoadsorption of anti