Prevelance, Genesis and Prognostic Relevance of Beta1-Adrenoceptor Autoantibodies in Human Myocardial Disease - Project description
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 autoanti-bodies 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 ab-normalities 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-AR, recently we provided conclusive evidence for a beta1-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 the nature and severity of the underlying myocardial disease, and
the sequence of events leading to the formation of functional receptor autoantibodies have not yet been systematically investigated.
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 antibodies depending on the underlying cardiac disease. A second goal is to clarify whether there is a link in humans between acute inflammatory or acute ischemic myocardial damage and the development of stimulating anti-beta1 antibodies (correlation of the severity of myocardial damage with occurrence, peak, and course (persistence) of beta1 autoantibody titers).
Implementation
Results from a first smaller pilot study clearly indicated that anti-beta1 abs may have an adverse effect on cardiac function in chronic heart failure. Ten years of clinical follow-up of the patients from this pilot study revealed, that anti-beta1 antibody-positive patients had an almost threefold increased cardiovascular mortality risk. In the last few years the basis for a larger prevalence study and thus re-evaluation of the predictive potential of anti-beta1 abs has been formed with the aid of the Competence Network of Heart Failure (CNHF) at the Cardiovas-cular Center in Würzburg. However, the so far available defined CNHF patient groups will be soon expanded by prospective inclusion of patients with acute myocarditis or acute myocardial infarction in the frame of a national multicentre study under the auspices of the CNHF. In the last few years we equally developed a novel highly sensitive method to detect and quantify antibody-induced receptor activation using fluorescence resonance energy transfer (FRET), which reliably identifies stimulating receptor-autoantibodies in humans. Moreover, the FRET methodology will facilitate the sequential analysis of larger patient cohorts. Our planned prospective study on the genesis and time-course of stimulating anti-beta1 abs after acute inflammatory or acute ischemic myocardial damage (ETiCS-study) will be funded in the frame of the BMBF-program “molecular diagnostics” and carried out in cooperation with the Center for Study Coordination, Study Management and Biometrics (CSSB) in Leipzig, and, of course, will include more than 10 established CNHF-network partners as well.
Added value via networking
Without the extensive database and bio-material bank of the CNHF and the biometrics at the CSSB the project would not be feasible. Conversely, for the CNHF there is considerable added value from the analysis of the biomaterials obtained in various CNHF-subprojects with a novel, highly sensitive autoantibody detection method contributed by subproject 6b. Our studies across the various projects will serve to acquire substantial knowledge on the development and pathophysiologic significance of autoimmunity in heart failure. In parti-cular, fruitful synergies are to be expected with CNHF-subproject 9a.