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Cardiac resynchronization therapy (CRT) has developed into a very effective technology for patients with decreased systolic function and has substantially improved patients’ clinical course. However, non-responsiveness to CRT, described as lack of reverse cardiac chamber remodeling, leading to lack to improve symptoms, heart failure hospitalizations or mortality, is common, rather unpredictable, and not fully understood. This article aims to discuss key factors that are impacting CRT response, from patient selection to LV lead position, to structured follow-up in CRT clinics. Secondly, common causes and interventions for CRT non-responsiveness are discussed. Next, insight is given into technologies representing new and feasible interventions as well as pacing strategies in this group of patients that remain challenging to treat. Finally, an outlook is given into future scientific development. Despite the progress that has been made, CRT non-response remains a significant and complex problem. Patient management in interdisciplinary teams including heart failure, imaging, and cardiac arrhythmia experts appears critical as complexity is increasing and CRT non-response often is a multifactorial problem. This will allow optimization of medical therapy, and the use of new integrated sensor technologies and telemedicine to ultimately optimize outcomes for all patients in need of CRT.

Treatment of cardiac resynchronization therapy non-responders: current approaches and new frontiers