Human cardiac myosin autoantibodies impair myocyte contractility: a cause‐and‐effect relationship

Abstract

The functional relevance of autoantibodies (Abs) against cardiac myosin (CM) in clinical idiopathic dilated cardiomyopathy (DCM) remains controversial. The study sought to determine effects of human Abs affinity-purified (AF) by immunoaffinity column chromotography on excitation-contraction coupling in isolated myocytes. Effects of CM-Abs from heart failure patients with DCM (n=19) and ischemic heart disease (IHD, n=19) on contractility, L-type Ca2+ current, and Ca2+ transients in continuously perfused rat ventricular myocytes were studied. Immunofluorescence studies using confocal microscopy were carried out to determine whether Abs were internalized. AF-Abs from either group did not differ in IgG titer but differed in their elution profiles. The IgG3 subclass response was higher in AF fractions from DCM (21%) than IHD (5%) patients. The Abs reduced the capacity of field-stimulated myocytes to contract in a dose-dependent manner. Inhibition of contraction, as a percentage of untreated cells, was greater with DCM than IHD-Abs (P=0.004), and the effect was independent of Ab titer. An increase in frequency of the beating myocytes (0.2 to 3.0 Hz) raised peak systolic and diastolic levels of [Ca2+]i of cells treated with DCM but not IHD-Abs (P<0.005). The AF-Abs were not internalized by myocytes and had no effect on L-type Ca2+ currents. The altered sensitivity of the myofilaments to [Ca2+]i by CM-Abs may represent a potential mechanism of autoantibody-mediated impairment in clinical DCM.

Autoantibodies in Heart Failure and Cardiac Dysfunction

“…66 To investigate the functional effects of antimyosin antibodies, Warraich et al affinity purified anticardiac myosin autoantibodies of patients with DCM or IHD. 67 When isolated cardiomyocytes were exposed to anticardiac myosin autoantibodies an altering of Ca 2ϩ -sensitivity of myofilaments and reduction of contractility of cardiomyocytes was observed. However, affinity-purified autoantibodies were not internalized by myocytes and had no effect on L-type Ca 2ϩ -currents.…”

The Role of B-Cells in Heart Failure

“…28 For example, antibodies against myosin and troponin I have been reported to be present in experimental models of autoimmune myocarditis, 29,30 in humans with dilated CMP, and in ischemic heart disease. [31][32][33] Other important antibodies reported in the literature include antimuscarinic receptor 2, antimitochondrial M7, anti-actin, and anti-heat shock protein 60 (HSP-60) ( Table 1). [34][35][36][37] In heart failure, HSP-60 present in the mitochondrial matrix will undergo translocation to the cellular membrane, where antibodies will bind and cause increased rates of apoptosis.…”

Discovering novel targets for autoantibodies in dilated cardiomyopathy

“…It is therefore evident that further investigation of this fatal condition, its pathomechanisms and future therapeutic strategies merit attention. A considerable percentage of human DCM cases appear to be autoimmune mediated [14] and direct pathogenetic contributions of autoantibodies have been demonstrated in nonhuman studies [12]. These findings have led to the therapeutic concept of autoantibody removal from DCM patients sera with striking success [9][10][11][24][25][26].…”

“…Given the increasing evidence for an autoantibody-mediated autoimmune reaction in human DCM patients [14,23], we analyzed the canine autoantibody repertoire from spontaneous DCM cases on atrial (Fig. 1a) and ventricular (Fig.…”

“…The presence of antiheart protein-specific autoantibodies had been already reported in about 25% of DCM patients in 1990 [8]. However, essential progress in assigning these autoantibodies as directly causative for DCM pathogenesis has occurred only recently: first, removal of heartspecific autoantibodies by immunadsorption leads to measurable amelioration of heart function in DCM patients [9][10][11], secondly the pathogenic potential of these autoantibodies has been shown by either adoptive transfer in experimental animals [12] or in cell culture experiments on isolated cardiomyocytes [13,14].…”