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TP 6b Prevalence, Genesis and Prognostic Relevance of Beta1-Adrenoceptor Autoantibodies in Human Myocardial Disease

Background

In heart failure, evidence is growing for a pathogenic significance of functionally active (auto-)antibodies being able to recognize and to stimulate the cardiac beta1-adrenergic receptor (anti-beta1 abs). Anti-beta1 abs are thought to play a key role particularly in the initiation and course of idiopathic dilated cardiomyopathy (DCM), a heart muscle disease of unknown etiology.

Patients with chronic heart failure (CHF) often present alterations in humoral and cellular immunity. Therefore, current theories on cardiac tissue injury in DCM focus on abnormal or misled immune responses to infections caused by cardiotropic viruses, bacteria, and/or parasites. As a consequence, a substantial number of CHF-patients develop cross-reacting antibodies and/or autoantibodies to a wide panel of cardiac antigens, including membrane proteins (i.e., cell surface receptors), mitochondrial proteins, and myocyte structural proteins. Irrespective of whether development of DCM is primarily due to chronic myocardial infection or to abnormalities in the adaptive or innate immune system, cardiac tissue injury is thought to be mediated mainly by cytokines and/or heart-specific autoantibodies. At least for antibodies directed against the human beta1-receptor, recently we provided conclusive evidence for a receptor-directed autoimmune attack as a possible cause of heart failure in a human-analogous rat model. However, in humans the true prevalence of stimulating anti-beta1 abs depending on nature and severity of the underlying myocardial disease, and the sequence of events leading to the formation of receptor autoantibodies have not yet been systematically analyzed.

Objective

The objective of our project is to assess the prevalence of functional anti-beta1 abs in larger, well-defined patient cohorts with heart failure of defined origin. The comparison of antibody status/antibody development (titer) and the clinical course of the disease will permit us to estimate the predictive potential of anti-beta1 abs depending on the underlying cardiac disease. A second goal is to clarify whether in humans there is a link between acute inflammatory or acute ischemic myocardial damage and the development of stimulating anti-beta1 abs (correlation of the severity of myocardial damage with occurrence, peak, and course (persistence) of anti-beta1 autoantibody titers).

Key results

Since 2009 the generation and clinical impact of human anti-beta1-abs is prospectively investigated in a multi-centre clinical diagnostic study. The so-called Etiology, Titer-Course and (effect on ) Survial of cardiac auto-antibodies (ETiCS)-study is funded by the German Ministry of Education and Research (BMBF) and currently implements a novel fluorescence-based detection method (FRET-assay) to follow both, the development and functional activity of anti-beta1-abs in patients with acute myocarditis or a first myocardial infarction.

Publications

  • Nikolaev VO et al. A novel fluorescence method for the rapid detection of functional beta1-adrenergic receptor autoantibodies in heart failure. J Am Coll Cardiol. 2007;50:423-31.
  • Deubner N et al. Cardiac beta1-adrenoceptor autoantibodies in human heart disease: rationale and design of the Etiology, Titre-Course, and Survival (ETiCS) Study. Eur J Heart Fail. 2010;12:753-62.
  • Jahns R et al. Targeting receptor antibodies in immune cardiomyopathy. Semin Thromb Hemost. 2010;36:212-8.
  • Jahns R: Autoantibodies directed against cardiac troponin I – Friend or Foe? (Editorial) Eur J Heart Fail. 2010;12, 645-48.
  • Holthoff HP et al. Measurement of anti-beta1-AR autoantibodies in heart failure by a cellular ELISA. Circ Res. 2012;111:675-84.

Perspectives

Embedded in the funding program „Molecular Diagnostics“ of the German Ministry of Education and Research (BMBF) the diagnostic Etiology, Titer-Course and Survial (ETiCS)-study is currently ongoing. By prospectively following large, well defined patient populations with either disease entity (inflammatory or ischemic cardiac damage) the results from the ETiCS study will provide deeper insights into the contribution of autoimmune processes to the initiation and/or progression of human heart disease/failure and, thereby, furnish a basis for the development of novel therapeutic strategies and agents specifically targeting cardio-noxious receptor auto-antibodies.

Contact

Prof. Dr. Roland Jahns
Universitätsklinikum Würzburg
Interdisziplinäre Biomaterial- und Datenbank Würzburg (ibdw)
Tel.: +49 (0)931 20146368
E-Mail: ed.grubzreuw-inu.kinilknull@r_snhaj