EXTRACELLULAR-MATRIX AND CYTOSKELETON OF THE MYOCARDIUM IN CARDIAC INFLAMMATION

The cardiac cytoskeleton and the extracellular matrix play an essentia l role for maintaining cellular integrity and function of the myocardi um. The network of microtubules and intermediate filaments are disrupt ed by the inflammatory reaction which depends on resident cells (myocy tes, fibroblasts, endothel cells) and on systemic cells (granulocytes, macrophages, monocytes, lymphocytes). Changes in the cardiac cytoskel eton and the extracellular matrix may affect contractile function, sin ce the cytoskeleton organizes the intra- and intercellular architectur e. The inflammation in heart disease and the induction of fibrosis are mediated by cytokines and growth factors derived from fibroblast acti vation and from the B- and T-cell activity. A possible connecting link for the induction of fibrosis is the presentation of the myocardial a ntigens to the immune system and its subsequent cellular and humoral a utoreactive response (Figure 1). Different autoantibodies to sarcolemm al and myolemmal antigens, to laminin, to extracellular matrix protein s, to the collagens and to myofibrils were demonstrated both in endomy ocardial biopsy and as circulating autoantibodies in the peripheral bl ood. The pathophysiological role of the cytoskeleton and the extracell ular matrix are well defined for beta-tubulin, fibronectin, laminin, d esmin, vimentin, vinculin and collagen: beta-tubulin is increased or a ltered in dilated cardiomyopathy (DCM). Fibronectin appears in irregul ar forms in DCM as well. Ultrastructural analysis showed an increased content of laminin in basement membranes. In addition anti-laminin ant ibodies were found in 73% of patients with myocarditis and in 78% of p atients with DCM. Desmin (z-bands) are partly destructed in DCM. Anti- desmin antibody titers as indicators of a possible secondary immune re sponse are found high in patients with acute myocarditis declining dur ing reconvalescence and are also elevated in DCM. The vimentin of the endothelial cells and the vinculin of the sarcolemmal membrane and the intercalated discs have been demonstrated to be irregularly shaped an d increased in content in DCM whereas in myocarditis their appearance and content is still unknown. The intracellular content of collagen ty pe 5 is increased in DCM and in myocarditis. The presence of autoantib odies to components of the cytoskeleton and the extracellular matrix i n myocarditis and perimyocarditis is well-described. Antibodies to the myolemma and the sarcolemma are found in almost all patients with per imyocarditis in the serum or bound in the biopsy. Some of them have be en known cytolytic in vitro to isolated heart cells. In pericarditis a shift to antibodies to the extracellular matrix, collagen and interme diate filaments is observed among the circulating antibodies. In patie nts who have undergone heart transplantation both circulating and boun d antibodies to sarcolemma and extracellular matrix were found in high degrees, even if no cellular rejection was present. Supporting the hy pothesis of a secondary immunpathogenesis of heart muscle disease afte r a viral infection, antibodies directed to the myolemmal or sarcolemm al sheath, which may be cytotoxic or cytolytic and also antibodies to collagen, fibronectin, laminin, actin and myosin have been demonstrate d. In acute rheumatic fever the immunological cross reactivity between heart-reactive antibodies to vimentin, myosin, cardiolipin and kerati n and cell wall components and the M-protein of group A streptococci i s well described. In chronic polyarthritis and ankylosing spondylitis with cardiac involvement heart specific anti-myolemmal antibodies have been reported. In infective endocarditis antibodies to collagen and o ther proteins of the extracellular matrix have been described. It can be derived from these data that the altered structure of the extracell ular matrix in these diseases may induce auto- or natural antibody for mation and uphold a chronic cellular immunoreactivity of low or modera te intensity.