According to the 2021 heart failure guidelines, digoxin carries a Class IIb recommendation (may be considered) in symptomatic patients despite optimal treatment with the so-called “big four” drug classes: ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), SGLT2 inhibitors (flozins), mineralocorticoid receptor antagonists (MRAs), and β-blockers [4]. The gene discussed is SLC5A2; the disease is heart failure.