The Role of Functional Active Anti-Angiotensin-Receptor 1 (ATR1)- and Anti-Endothelin-Receptor A (ETRA)-Antibodies and Autoreactive T Cells in Cardiomyopathy

1. AIM OF THE STUDY 1.1. Background Progressive interstitial fibrosis parallels pathological remodeling in the failing heart. This is particularly the case in patients with post-inflammatory dilated cardiomyopathy, but is also observed in ischemic and hypertensive heart disease. Both, Angiotensin II (AngII) and Endothelin-1 (ET1) induce the formation of the profibrotic cytokine TGFβ and promote fibrosis. From this point of view, it is not surprising that blocking the Renin-Angiotensin-Aldosterone-System (RAAS) evolved as key strategy to slow heart failure progression. Furthermore, recent data also points to an important role of Angiotensin II signaling in heart failure with preserved ejection fraction. In animal models, blocking the effect of AngII or ET1 reduces fibrotic remodeling following myocardial ischemia or in pulmonal hypertension. In line with these findings, we found no evidence of fibrotic remodeling in AGTR1-/- mice who recovered from acute myocarditis. Nevertheless, RAAS blockade is not efficient enough to completely prevent heart failure progression or even rapid deterioration in subgroups of the affected patients. Only recently, Riemekasten et al demonstrated that auto-antibodies against AGTR1 and ETAR are increased in systemic sclerosis and associated with increased pulmonary hypertension and lung fibrosis (2). Moreover, these auto-antibodies were shown to be functional active and to induce downstream expression of TGFβ -mRNA.

Anti-AGTR1-Ab and Anti-ETAR-Ab might therefore directly promote fibrosis through activation of AGTR1 and ETAR. Furthermore, auto-reactive T-cells to the myosin heavy chain (MyHC) of the heart muscle were demonstrated to play an important role in both the initial inflammation during myocarditis as well as the progression of inflammation.

1.2. Rationale for the current study Cardiac autoantibody titers are generally elevated in patients after myocardial infarction or suffering from systolic heart failure. In addition, we found experimental evidence for a critical role of AngII signaling in the development of cardiac fibrosis. We hypothesize that auto-immunological effects in general, and Anti-AGTR1-Ab, Anti- ETAR-Ab and auto-reactive T-cells in particular, are important and so far widely underestimated in the pathogenesis of cardiomyopathies and that they interfere with evidence based treatment approaches.

1.3 Aims The objectives of this study are to

• determine the concentration of Anti-AGTR1- and Anti-ETRA-AB in the patients blood.
• determine the auto-reactive heart specific T-cells and their cytokine expression profile in patients blood.
• to correlate these findings to outcome (hospitalizations due to heart failure, stroke, myocardial infarction, and death) and to cardiac function of the patient (VO2, Ejection fraction, NYHA class).

2. STUDY DESIGN Prospective pilot study.
3. PARTICITPANT ENTRY 3.1. Pre---registration evaluation Patients with cardiomyopathy and heart failure for 6 months or more will be recruited at the GZO Spital Wetzikon during ambulatory visits.
4. EFFICACY AND SAFETY VARIABLES 4.1. Efficacy variables and examinations 4.1.1 non---study specific variables and examinations Medical history

• general information: age, gender, weight, height
• actual medications
• staging of heart failure according to the severty of symptoms and physical activity (New York Heart Association-classification) Electrocardiogram (ECG) For all electrocardiographic recordings a commercially available 12-lead ECG will be used and set at 25mm/s paper speed and 10mm/mV amplitude.