Cardiac remodelling in the era of the recommended four pillars heart failure medical therapy

: Cardiac remodelling is a key determinant of worse cardiovascular outcome in patients with heart failure (HF) and reduced ejection fraction (HFrEF). It affects both the left ventricle (LV) structure and function as well as the left atrium (LA) and the right ventricle (RV). Guideline recommended medical therapy for HF, including angiotensin-converting enzyme inhibitors/angiotensin receptors II blockers/angiotensin receptor blocker-neprilysin inhibitors (ACE-I/ARB/ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i), have shown to improve morbidity and mortality in patients with HFrEF. By targeting multiple pathophysiological pathways, foundational HF therapies are supposed to drive their beneficial clinical effects by a direct myocardial effect. Simultaneous initiation of guideline directed medical therapy (GDMT) through a synergistic effect promotes a 'reverse remodelling', leading to a full or partial recovered structure and function by enhancing systemic neurohumoral regulation and energy metabolism, reducing cardiomyocyte apoptosis, lowering oxidative stress and inflammation and adverse extracellular matrix deposition. The aim of this review is to describe how these classes of drugs can drive reverse remodelling in the LV, LA and RV and improve prognosis in patients with HFrEF.