Autoantibodies against the  -adrenergic receptor in human myocarditis and dilated cardiomyopathy:  -adrenergic agonism without desensitization

Abstract

The serum of patients with myocarditis and dilated cardiomyopathy contains immunoglobulins capable of causing in vitro acceleration of beating of neonatal rat heart myocytes. This effect is stereoselectively inhibited by (-)-propranolol and is inhibited also by the beta 1-selective adrenergic antagonists, bisoprolol and metoprolol. This effect is not reversed by washing and continues unabated for at least 24 h.

Mimicry and Antibody-Mediated Cell Signaling in Autoimmune Myocarditis

“…In this study, Ab-mediated activation of PKA was identified in a rat heart cell line and was shown to be mediated by both ␤1-and ␤2-AR. These results are consistent with previous reports suggesting that sera from myocarditis and cardiomyopathy patients contain agonistic autoantibodies that bind to ␤-AR (34,37). Adrenergic receptors, especially ␤1 subtype, not only function to generate second messengers to control the heart contractility, but also to regulate other cardiac functions, myocyte growth, and programmed cell death.…”

“…Circulating cardiac autoantibodies to CM and other heart-specific autoantigens are markers of autoimmunity in human myocarditis (11,12,(32)(33)(34)(35)(36). In mice, deposition of CM-reactive Abs in the myocardium was detected after immunization with CM (26).…”

Foreword to special issue on “Myocarditis”

“…Meanwhile, the first experimental observations were made by several investigators, suggesting a possible involvement of autoimmune mechanisms to cardiac autoantigens; in particular, a mouse model for myosin-induced autoimmune myocarditis was described by the Neu et al [5]. In addition, various groups in the late 80s and early 90s reported the presence of circulating anti-heart autoantibodies against myosin as well as other autoantigens in acute and chronic myocarditis or dilated cardiomyopathy, in keeping with the hypothesis of autoimmunity being involved in a subset of patients [6][7][8][9][10][11][12][13][14]. A retrospective multicenter registry from the USA coordinated by Cooper et al [15] reported the efficacy of immunosuppressive therapy in a rare but lethal form of myocarditis, e.g., giant cell myocarditis.…”

Acute Myocarditis – A Trigger of Cardiac Autoimmunity? Expected Insights from the Etiology, Titre-Course, and Effect on Survival of Cardiac Autoantibodies (ETiCS) Study

“…In addition, functional tests revealed that such anti-beta1-ECII may also act as allosteric regulators of beta1-adrenoceptor activity through modulation of cellular cAMP-production and/or cAMP-dependent protein kinase (PKA) activity (Wallukat et al, 1991;Limas et al, 1992;Jahns et al, 1999;Nikolaev et al, 2007). The use of different screening-techniques renders direct comparisons of the available data difficult, however.…”

“…Hence, so far reported prevalences should be always interpreted in the context of the detection method utilised. Nevertheless, taken all these reports together, there is wide consent that a substantial fraction of patients with DCM and ICM, but only very few healthy subjects have ciculating functionally active adrenoceptor-aabs (Wallukat et al, 1991;Magnusson et al, 1994;Jahns et al, 1999). An association of such aabs with impaired cardiac function (Jahns et al, 1999), a higher incidence of ventricular arrhythmias (Iwata et al, 2001;Störk et al, 2006), and a higher incidence of sudden cardiac death (Iwata et al, 2001) have been demonstrated.…”