CHRONIC HEART FAILURE: PATHOPHYSIOLOGY OF NEUROHORMONAL ACTIVATION, DIAGNOSTIC CLASSIFICATION, AND EVIDENCE-BASED PHARMACOLOGICAL AND DEVICE THERAPY

Background: Chronic heart failure (CHF) is a clinical syndrome affecting over 64 million people globally, characterized by structural or functional cardiac abnormalities that impair ventricular filling or ejection, producing symptoms of dyspnoea, fatigue, and fluid retention. Despite advances in therapy, 5-year mortality exceeds 50%, surpassing many cancers. The neurohormonal model—activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) as maladaptive responses to reduced cardiac output—has driven the development of four drug classes that have transformed HF with reduced ejection fraction (HFrEF) outcomes. Objective: To provide a concise, evidence-based review of the pathophysiology of neurohormonal activation in CHF, the ESC 2021 diagnostic classification, biomarker-guided diagnosis, and evidence-based pharmacological (ACE inhibitors, beta-blockers, MRAs, SGLT2 inhibitors, ARNi) and device therapies for HFrEF. Methods: A systematic review of eight primary sources—pivotal randomized clinical trials, meta-analyses, and authoritative ESC guidelines published between 1987 and 2024—was conducted. Results: Four drug classes constitute the HFrEF cornerstone: ACE inhibitors (↓mortality 23%, CONSENSUS/SOLVD), beta-blockers (↓mortality 34%, MERIT-HF/COPERNICUS), mineralocorticoid receptor antagonists (MRAs, ↓mortality 30%, RALES/EMPHASIS-HF), and SGLT2 inhibitors (↓CV death/worsening HF 25%, DAPA-HF/EMPEROR-Reduced). Sacubitril/valsartan (ARNi) reduces the composite CV death/HF hospitalization by 20% over ACE inhibitors alone (PARADIGM-HF). NT-proBNP > 125 pg/mL (outpatient) or > 450 pg/mL (acute) is the primary biomarker for HF diagnosis and monitoring. Cardiac resynchronization therapy (CRT) reduces mortality by 36% in patients with LBBB and QRS ≥ 150 ms. Conclusion: HFrEF management has been transformed by four evidence-based drug classes and device therapy that reduce mortality, hospitalization, and symptoms through neurohormonal blockade and reverse cardiac remodelling. The emerging 'fantastic four' regimen (ACEi/ARNi + beta-blocker + MRA + SGLT2i) now defines optimal medical therapy and should be initiated simultaneously at low doses rather than sequentially in all eligible HFrEF patients.