I. CRT treatment significantly improves prognosis in patients with reduced ejection fraction heart failure One of the most dramatic advances in cardiovascular therapy in the past 20 years has been the use of cardiac resynchronization therapy (CRT) in the treatment of patients with reduced ejection fraction heart failure (HFrEF). A series of studies have shown that CRT significantly improves the prognosis of patients with New York Heart Function Class III-IV HFrEF. The MADIT-CRT study verified whether patients with HFrEF with mild symptoms also benefit from CRT treatment. In a study that included >1000 patients, the incidence of the primary endpoint (heart failure event or death) was 17.2% and 25.3% in the CRT-treated and control groups, respectively. This finding was subsequently supported by another study in which CRT reduced heart failure events and mortality. Current guidelines recommend CRT for all patients with HFrEF with prolonged QRS (>150ms). Second, the ARB-enkephalin inhibitor LCZ696 is expected to replace ACEI as the standard treatment for heart failure. In terms of drug therapy, enkephalin inhibitors exert diastolic, anti-fibrotic and urinary sodium excretion effects by amplifying the physiological effects of endogenous enkephalin. The combination of enkephalin inhibitors with ACEI has not been successful due to study design flaws and deviations from the intended target effect, but the combination with ARB appears to overcome these risks and achieve the monotherapeutic effect of ARB. The PARADIGM-HF study was designed to investigate whether the ARB-enkephalin inhibitor LCZ696 is superior to standard treatment with enalapril in the treatment of patients with HFrEF. Patients were randomized to receive LCZ696 (200 mg, 2/day) and enalapril (10 mg, 2/day) with the study endpoint of cardiovascular death or heart failure admission. The study showed that LCZ696 reduced the incidence of the primary endpoint event, and LCZ696 is expected to replace ACEI as the standard of care for patients with HFrEF. The clinical benefit of beta blockers for heart failure may be due in part to their heart rate lowering effect. The study was designed to compare whether the addition of ivabradine (an If channel blocker) to a beta blocker reduced the primary endpoints of cardiovascular death or hospitalization for heart failure. The results of the study showed an event rate of 24% and 29% for the primary endpoint in the ivabradine and placebo groups, respectively. This benefit was eliminated with increasing doses of beta blockers, possibly because full beta blocker treatment offset the heart rate lowering effect of increasing ivabradine. Ivabradine is now approved for use in patients with symptomatic HFrEF and sinus rhythm greater than 70 beats/min as adjunctive therapy to ACEI, beta blockers, and aldosterone receptor antagonists. IV. Aldosterone receptor antagonists improve prognosis in patients with mild symptomatic HFrEF Aldosterone receptor antagonists improve survival in patients with advanced HFrEF and post-infarction heart failure, but their role in patients with mild symptomatic HFrEF is unclear, and EMPHASISHF is aimed at patients with mild symptomatic HFrEF. 2737 New York patients in the EMPHASISHF study were included. cardiac function class II patients and compared the efficacy of eplerenone with placebo. Only 18.3% of patients in the eplerenone group met the primary endpoint (cardiovascular death or heart failure admission) after a mean follow-up of 21 months, compared with 25.9% in the placebo group, and the trial was therefore terminated early. Importantly, such benefit was an additional benefit with ACEI and β-blocker therapy, and thus, aldosterone receptor antagonists have become authorized therapeutic agents for patients with mild HFrEF. V. No progress in the treatment of ejection fraction preserved heart failure In contrast to the field of HFrEF research, pharmacological treatment of ejection fraction preserved heart failure (HFpEF) has so far been ineffective in reducing major adverse events. Given the benefits of aldosterone receptor antagonists in patients with HFrEF, researchers conducted the TOPCAT study to evaluate the efficacy of ambrisentin in patients with heart failure with an ejection fraction greater than 45%. The results of the study showed no significant difference in the primary endpoint (cardiovascular death, cardiac arrest, or hospitalization for heart failure) between the ambrisentin group and the placebo group, except for patients who were enrolled in the study due to elevated B-type brain natriuretic peptide. This result implies that patients who met all criteria for “heart failure admission” but did not have elevated BNP may not be true HFpEF patients and therefore would not benefit from aldosterone receptor antagonist therapy. Defining the true role of aldosterone receptor antagonists in patients with HFpEF requires recruiting a more homogeneous patient population and confirming the diagnosis of true HFpEF. Improving iron deficiency may benefit patients with heart failure The concept of improving the prognosis of heart failure by treating heart failure comorbidities, including the correction of heart failure-related anemia and iron deficiency, is gaining increasing attention. Erythropoietin-stimulating drugs are commonly used to treat anemia, but studies have shown no reduction in major cardiovascular events in heart failure patients. In contrast, correction of iron deficiency has led to encouraging results.The FAIR-HF study included 459 HFrEF patients with combined iron deficiency (based on serum ferritin or transferrin saturation) who were randomized to intravenous iron and saline groups. The results showed improvement in 50% of the intravenous iron supplementation group (based on overall patient assessment) compared to 28% of the placebo group. However, no studies have evaluated the effect of intravenous iron supplementation on mortality in HFrEF patients with combined iron deficiency. VII. Hope for the treatment of acute heart failure is still far away Acute heart failure treatment can be considered unchanged for more than 40 years, with a large number of proposed drugs favoring urinary sodium excretion at the cost of compromised renal function and with no significant prognostic benefit. Relaxin is an endogenous peptide with diuretic, sodium excretory, vasodilatory and antifibrotic effects. RELAXAHF enrolled 1061 patients randomized to the serelaxin (recombinant relaxin) and placebo groups. serelaxin improved dyspnea but did not affect the 60-day readmission rate/cardiovascular and renal mortality of patients, but the study found fewer 180-day deaths and less worsening of in-hospital heart failure in the serelaxin group. Based on these results, the administration did not approve the drug, but the study’s findings were sufficient to drive a trial addressing final mortality, which is exactly what the RELAX-II study is doing and is currently underway. VIII. Gene therapy is beginning to make its mark Gene therapy for heart failure is coming into focus, and insertion of the SERCA2a gene into the heart in heart failure may be a therapeutic strategy, as the SERCA2a gene plays an important role in myocardial contraction The CUPID study included 39 patients with heart failure receiving intracoronary injections of SERCA2a type 1 adeno-associated virus or placebo. Initial results suggest that gene transfection may improve related surrogate endpoints and reduce cardiovascular events. A CUPID2 study enrolling additional patients is currently underway. IX. Biomarkers may better guide heart failure treatment The discovery of biomarkers implies a shift in risk factors for left ventricular insufficiency and may change the diagnosis of heart failure in the future Researchers from the STOP-HF study conducted a BNP screening program in which 1,374 high-risk asymptomatic patients were randomized to treatment based on blood BNP levels and to usual care. The results of the study showed that the incidence of left ventricular insufficiency was 5.3 percent and 8.7 percent in the BNP and conventional treatment groups, respectively, after 4.2 years. Other biomarkers, including stage specific markers for the development of left ventricular insufficiency (e.g. ST2 and galectin-3), are also being investigated. X. Tracking patient condition for early intervention Over the past 10 years, tremendous technological advances have been made in tracking patient condition. In a meta-analysis that included more than 2,000 patients with HF running EF and HFrEF, BNP-guided heart failure therapy significantly reduced all-cause mortality and heart failure admissions in patients under 70 years of age. Remote tracking of patient condition, such as pulmonary artery pressure measurement using the CardioMEMS™ Heart Failure System can further complement biomarker-guided therapy and ensure early intervention. XI. Summary Over the past decade, heart failure treatment has made great strides and the prognosis of patients with HFrEF is improving with the advent of new drugs, devices and interventions as well as evolving cellular and gene therapies. However, breakthroughs in the treatment of acute heart failure and HFpEF remain elusive. In the future, individualized medicine that integrates neurohormones, proteomics, metabolomics, and genomic information to develop treatment plans will be the focus of research.