During the last century the characteristics of patients with heart failure (HF) and acute HF (AHF) have shifted from patients with severe pump failure due to rheumatic, hypertensive and ischemic heart disease to older and more obese patients with multiple severe comorbidities. The pathophysiology of AHF has shifted in parallel from that of advanced, end-stage, pump failure caused by severe left ventricular dysfunction to age, obesity and comorbidity-related cardiovascular dysfunction combined with neurohormonal and inflammatory dysregulation or "inflammaging". With the advent of neurohormonal blockers leading to improved outcomes of patients with chronic HF, the focus of AHF therapy has also changed from care directed at early symptom improvement to therapies directed towards longer-term improvements in quality of life and outcomes. Studies conducted in the last 5 years suggest that the beneficial effects seen with the 4 pillars of guideline-directed medical therapy for HF, mostly comprising neurohormonal blockade, can be extended to AHF when these therapies are initiated and rapidly uptitrated during admission and after discharge. A recent pilot study (CORTAHF) has suggested that these benefits can be extended by treating patients with AHF and markers of inflammatory activation with anti-inflammatory therapies. Future studies should further examine whether combined anti-inflammatory therapy and neurohormonal blockade can lead to reversal of disrupted underlying pathophysiology and remission in patients with AHF.