The role of ?-adrenergic system remodeling in human heart failure: A mechanistic investigation

?-adrenergic receptor antagonists (?-blockers) are extensively used to improve cardiac performance in heart failure (HF), but the electrical improvements with these clinical treatments not fully understood. The aim of this study was analyze electrophysiological effects system remodeling reduced ejection fraction and underlying mechanisms. We a combined mathematical model that integrated signaling electrophysiology calcium cycling human ventricular myocytes. HF remodeling, both systems, introduced quantitatively changes properties due stimulation receptors failing found inotropic effect altered Ca2+ dynamics resulting from combination structural, remodeling. Isolated cells showed proarrhythmic risk after sympathetic because early afterdepolarizations appeared, vulnerability greater When analyzing coupled cells, transmural repolarization gradients between endocardium epicardium normal tissue, less effective at reducing comparison selective activation isoforms revealed response ?2-adrenergic blunted while ?1-adrenergic downstream effectors regulated most observed stimulation. In conclusion, able reproduce an activity on myocytes explain mechanisms involved. derived predictions could help treatment guide design future experiments.