This is a retrospective analysis of nine clinical trials spanning a wide period (from the CASTLE-AF trial initiated in 2008 to the ongoing BIO|Stream.HF) and encompassing important developments in HF therapy and management over the years, including the introduction of sodium-glucose co-transporter-2 inhibitors and mineralocorticoid receptor antagonists (not specifically reported here). The gene discussed is NR3C2; the disease is atrial fibrillation.