Inhibition of the endothelin A receptor was hailed many years ago as a promising therapeutic principle for the treatment of chronic heart failure, because numerous experimental studies in animal models had pointed to this.
To date, clinical studies have not been able to confirm those findings. DZHK investigators led by Johannes Backs at the partner site Heidelberg/Mannheim hypothesized that endothelin A receptor antagonists have failed to offer any benefit in clinical applications because standard treatment of the study participants with beta-adrenergic receptor blockers may have interfered with their action. The researchers have now shown that the endothelin A receptor in sympathetic neurons but not in cardiomyocytes is responsible for the progression of heart failure. In a new genetic mouse model and in cell models, they were able to show that in sympathetic neurons the endothelin A receptor reduces the re-uptake of the stress hormone norepinephrine thereby increasing the effective concentration of norepinephrine at the beta-adrenergic receptors. This results in activation of specific epigenetic signaling pathways in cardiomyocytes. Through this mechanism endothelin regulates adverse remodeling processes in the cardiomyocytes. According to the authors, these findings warrant new clinical studies to examine the efficacy of endothelin A antagonists in chronic heart failure. The investigators now aim to develop a personalized approach. Using a technique which was applied in the mouse study but which is also established in the clinical setting, they aim to identify a patient cohort that responds specifically to endothelin A receptor antagonists. The fact that such drugs are already being used in the clinic to treat other diseases, for example pulmonary hypertension, means that a time-consuming clinical safety evaluation is not required.
September 2014