In heart failure (HF) with reduced ejection fraction (HFrEF), four classes of drugs, the so-called fantastic four, also known as β-blockers, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and the most recent Sodium–Glucose Co-Transporters 2 Inhibitors (SGLT2is), have demonstrated positive results in randomized controlled trials (RCTs) [1,2]. The gene discussed is ACE; the disease is heart failure.