Heart failure in 2025: new insights, therapies, and clinical directions

Introduction

Background

Heart failure (HF) is a clinical syndrome characterized by typical symptoms and/or signs arising from structural or functional cardiac abnormalities, usually supported by elevated natriuretic peptides and objective congestion findings (1). It is still the leading cause of mortality and morbidity with high use of resources and healthcare costs, affecting between 1% and 3% of the total population, equating to an estimated 56.2 million [95% confidence interval (CI): 46.45–67.79] individuals (2). The management of HF reveals the success of translational medicine, where the understanding of neurohormonal pathways has been translated into pharmacotherapies that help improve the clinical outcome of patients. For example, the quadruple therapy, including angiotensin receptor-neprilysin inhibitor (ARNI) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), evidence-based beta-blocker, mineralocorticoid antagonist (MRA), and sodium-glucose cotransporter-2 inhibitor (SGLT2i), is the basic therapy to improve the lives of patients with heart failure with reduced ejection fraction (HFrEF) (3-5). Emerging evidence also recommends the addition of soluble guanylate cyclase stimulator, such as Vericiguat, as the fifth basic pharmacotherapy for those patients (6).

Rationale and knowledge gap

Despite the rapid advances in treatment, patients remain at a 40% annual risk of HF-related rehospitalization and a 28% risk of 3-year all-cause mortality even when treated with contemporary guideline-directed medical therapy (GDMT) (7,8). Therefore, there’s an urgent need for more research on the treatment of HF. The year 2025 has witnessed the completion of multiple landmark studies on the treatment and management of HF from different perspectives, providing new insights in HF treatment and promising solutions to clinical challenges. A comprehensive integration is urgently needed to summarize findings in the past year and elucidate how these updates refine HF management.

Objective

This article aims to synthesize important findings and updates concerning HF in 2025, including epidemiological trends, etiologies, risk factors, and the diverse spectrum of treatments. Through the integration of up-to-date research, this review proposes to provide a timely, evidence-based update for clinical practice and further investigation in HF.

Epidemiology, causes and risk factors

Understanding the global epidemiological landscape and etiologies of HF is essential for identifying high-risk populations and developing targeted prevention strategies, which accounts for the continuous emergence of studies in 2025. Results from these studies reveal that the global burden of HF remains substantial and is growing, driven by aging populations and the increasing prevalence of underlying cardiovascular and metabolic diseases, and is a major challenge in the United States. The HF STATS 2024 report shows that approximately 6.7 million adults aged 20 and older are currently living with HF, with prevalence rising sharply among those aged 65 and above. The lifetime risk of HF for U.S. adults is 24%. Major contributing etiologies include hypertension, coronary artery disease, and diabetes. The report projects that the number of HF patients will increase to 8.5 million by 2030 (9,10).

In China, a comprehensive 34-year subnational analysis revealed a 208.4% surge in prevalent HF cases, reaching an estimated 14.3 million in 2023. The etiological profile has shifted, with ischemic heart disease (IHD) now the leading cause, followed by hypertensive heart disease (HHD) and chronic obstructive pulmonary disease (COPD). Significant regional disparities exist, with northern provinces bearing higher IHD-related burdens and western provinces facing greater COPD-related impacts (11).

HF, representing the common terminal pathway for most cardiac diseases, arises from a spectrum of established etiologies and modifiable risk factors. The classic etiologies contributing to HF include IHD, hypertension, valvular heart disease, rheumatic heart disease, dilated cardiomyopathy, arrhythmia and congenital heart disease (2,12). Contemporary research further refines our understanding of etiology-phenotype associations. A newly published study elucidated that IHD was the dominant cause in patients with HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF), whereas hypertensive and valvular etiologies were more prevalent in heart failure with preserved ejection fraction (HFpEF). Furthermore, the etiologies most strongly associated with the composite endpoint of death or HF hospitalization were ischemic in HFrEF, hypertensive in HFmrEF, and valvular in HFpEF (13).

The recognized risk factors for HF encompass diabetes, obesity, chronic kidney disease (CKD), smoking, and alcohol consumption (12). Studies in 2025 have provided updated insights into these risks, particularly regarding sex-specific contributions. The PREVEND study at 25 years revealed significant sex-based differences in risk factors. In women, 71% of new-onset HFrEF cases were attributable to eight key risk factors (hypertension, hypercholesterolemia, obesity, smoking, atrial fibrillation, CKD, myocardial infarction, and diabetes), compared to 60% in men. For new-onset HFpEF, these same factors accounted for 64% of cases in women and 46% in men. A critical commonality emerged: hypertension and hypercholesterolemia were the strongest risk factors for HFrEF across sexes, while hypertension and obesity were the predominant risks for HFpEF (14).

The risk factors of HF continue to be a subject of investigation. A 2025 study on alcohol consumption presented a counterintuitive finding, reporting that low to moderate alcohol intake was associated with a reduced risk of incident HF (15). Concurrently, emerging research has identified several novel or less conventional risk factors. Studies have implicated CD40 agonists, specific patterns of ventricular ectopy (particularly those originating from the left ventricle and epicardial sites), alterations in specific gut microbiota, and even marital discord as contributors to increased HF risk (16-20). Collectively, these evolving findings deepen our comprehension of the multifactorial pathogenesis of HF (Figure 1).

Figure 1 Etiologies and risk factors of HF: established perspectives and 2025 updates. Figure 1 provides a comprehensive overview of the etiologies of HF, comparing conventional knowledge with breakthroughs reported in 2025. The left panel summarizes established etiologies such as IHD, hypertension, and valvular diseases, along with classic modifiable risk factors including diabetes, obesity, and smoking. The right panel highlights evolving insights from 2025, including etiology-phenotype association, sex-specific risk contributions, and novel factors discovered in 2025. Created in BioRender. Shen Z. [2026] https://BioRender.com with credit/m5n7dfi. HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IHD, ischemic heart disease.

Classification

Following the identification of HF, precise classification based on ventricular function or clinical stages is the cornerstone of appropriate treatment. According to the reports of several international HF associations, the classification of HF is mainly based on the left ventricular ejection fraction (LVEF) or the stage of disease. By LVEF, four groups are commonly used: HFrEF (≤40%), HFmrEF (41–49%), HFpEF (≥50%), and heart failure with improved ejection fraction (HFimpEF) (baseline ≤40%, increase by at least 10 percentage points, and follow-up >40%) (1). Such functional stratification is pivotal for guiding therapeutic strategies. While treatment for patients with HFrEF should center on the early initiation of “quadruple therapy”, treatment for HFpEF and HFmrEF mainly involves sodium-glucose cotransporter-2 (SGLT2) inhibitors and diuretics. Importantly, the management of HFimpEF necessitates the continued use of GDMT in spite of the improvement in LVEF. Additionally, recent research has proposed a novel HF category, HF with supra-normal ejection fraction (HFsnEF), defined by a LVEF of ≥65%. This group exhibits distinct clinical and echocardiographic characteristics and is associated with worse clinical outcomes, suggesting its potential as a unique diagnostic entity (21).

Based on the stage of disease, the American College of Cardiology/American Heart Association (ACC/AHA) stages are categorized as follows: Stage A comprises patients at high risk for HF but without structural heart disease or symptoms of HF; Stage B, structural heart disease without signs or symptoms of HF; Stage C, structural heart disease with prior or current symptoms of HF; and Stage D, refractory HF requiring specialized interventions (22,23). Therapeutic strategies vary across different clinical stages. Stage A focuses exclusively on risk factor modification, including hypertension control and lifestyle interventions. In Stage B, treatment progresses to ACEIs/ARBs/ARNIs and β-blockers, targeting subclinical structural abnormalities before symptom onset. Stage C necessitates the initiation of comprehensive GDMT, reflecting a fundamental transition from prevention to disease modification. Finally, Stage D represents a paradigm shift toward advanced therapeutic strategies, such as mechanical circulatory support, transplantation evaluation, and palliative care, since conventional pharmacotherapy becomes insufficient (3).

Treatment

The clear classification of HF provides a robust foundation for precise medical treatment, while the global burden highlights the importance of innovative therapeutic strategies. In the past year, the completion and conduction of substantial large-scale clinical trials have provided numerous novel insights into the treatment of HF, including pharmacotherapy, surgery, and new therapeutic devices. The emergence of state-of-the-art therapies is thrilling as well (Table 1).

Pharmacotherapy

Renin-angiotensin system inhibitor (RASi)

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi (24). With regard to HFrEF due to Chagas disease, the efficacy and safety of guideline-recommended treatments are uncertain. The PARACHUTE-HF trial compared the clinical outcomes between sacubitril/valsartan and enalapril. In this trial, 462 participants received sacubitril/valsartan and 460 received enalapril. Cardiovascular death occurred in 110 (23.8%) versus 117 (25.4%) patients, and first HF admission in 102 (22.1%) versus 111 (24.1%), respectively (25). In conclusion, there was no significant difference in clinical outcomes between sacubitril/valsartan and enalapril in patients with HFrEF due to Chagas disease.

Another analysis of a clinical trial concerning sacubitril/valsartan focused on its potential to attenuate the lowered haemoglobin levels and occurrence of incident anaemia caused by RASi in patients with HFmrEF or HFpEF. Within the PARADIGM-HF cohort of 4,795 individuals, sacubitril/valsartan significantly attenuated hemoglobin reduction (mean difference 0.1 g/dL; 95% CI: 0.0–0.2; P=0.005), lowered new anemia incidence [30.3% vs. 37.6%; hazard ratio (HR) 0.76; 95% CI: 0.68–0.85; P<0.001], and reduced iron therapy initiation (8.1% vs. 10.0%; HR 0.81; 95% CI: 0.67–0.97; P=0.03) (26). These findings underscore that sacubitril/valsartan may offer superior hematological protection compared to traditional RASis, particularly in mitigating anemia risk and the subsequent clinical demand for iron supplementation in this vulnerable population.

Nonsteroidal mineralocorticoid receptor antagonists (MRAs)

In 2024, the outcomes from the FINEARTS-HF trial revealed that finerenone treatment resulted in a significantly reduced rate of worsening HF events and cardiovascular death (27). Further analysis and trials done in 2025 have provided comprehensive insights into the therapeutic effects of finerenone. FINEARTS-HF analysis showed that the therapeutic effects of finerenone were irrespective of baseline New York Heart Association (NYHA) functional class, left atrial size, KDIGO (Kidney Disease: Improving Global Outcomes) risk categories, atrial fibrillation, and the concomitant use of an SGLT2i (28-32). Further real-world study demonstrated that in HFpEF patients with CKD, finerenone treatment was associated with significantly improved survival and fewer HF-related events without increasing cardiovascular or renal adverse events (33). Another real-world study comparing finerenone and spironolactone came to the conclusion that finerenone was associated with lower rates of hospitalization, mortality, acute kidney injury (AKI), and hyperkalemia (34). Findings of the research suggest promising prospects of finerenone in the treatment of HF.

SGLT2i

SGLT2 inhibitors are established therapies that lower the risk of worsening HF and cardiovascular events in outpatients (35). The DAPA ACT HF-TIMI 68 trial further investigated the efficacy and safety of in-hospital initiation of dapagliflozin in patients hospitalized for HF and randomly assigned 2,401 patients with HF to dapagliflozin or placebo. The primary endpoint (cardiovascular death or first worsening HF event) occurred in 10.9% with dapagliflozin and 12.7% with placebo (HR 0.86; 95% CI: 0.68–1.08; P=0.20). Specifically, worsening HF events occurred in 115 (9.4%) patients in the dapagliflozin group and in 122 (10.3%) patients in the placebo group (HR, 0.91; 95% CI: 0.71–1.18). Cardiovascular death was 2.5% versus 3.1% (HR 0.78), and all-cause mortality 3.0% versus 4.5% (HR 0.66). Altogether, these findings demonstrate no benefit from in-hospital initiation of dapagliflozin in reducing the risk of death from cardiovascular causes or worsening HF. Nevertheless, initiation of SGLT2 inhibitors during hospitalization may confer an early benefit by reducing the short-term risks of cardiovascular death, worsening HF, and all-cause mortality (36).

Soluble guanylate cyclase stimulators

Oral soluble guanylate cyclase stimulators target the nitric oxide-soluble guanylate cyclase-cGMP (3',5'-Cyclic guanosine monophosphate) signalling pathway and offers a mechanism distinct from standard neurohormonal blockade. The VICTOR trial randomized 6,105 ambulatory patients with HFrEF without recent worsening to vericiguat or placebo. Vericiguat treatment did not reduce the occurrence of the primary endpoint (cardiovascular death or HF hospitalization), which occurred in 18.0% and 19.1% of patients in the vericiguat group and placebo group respectively (HR 0.93; 95% CI: 0.83–1.04; P=0.22). However, cardiovascular mortality was reduced by vericiguat treatment (9.6% vs. 11.3%; HR 0.83; 95% CI: 0.71–0.97) (6). These conclusions offered a comprehensive understanding of vericiguat treatment for ambulatory HF patients.

Cardiac glycoside

Considering the uncertain therapeutic efficacy of the cardiac glycoside digitoxin in patients with HFrEF, the DIGIT-HF trial was conducted and revealed that treatment with digitoxin reduced the combined risk of all-cause death or hospital admission for worsening HF compared with placebo among patients with HF and reduced ejection fraction who received GDMT. Regarding the primary endpoint, the digitoxin cohort demonstrated a lower event rate compared to the placebo arm (39.5% vs. 44.1%; HR: 0.82; 95% CI: 0.69 to 0.98; P=0.03). All-cause mortality was documented in 167 patients (27.2%) in the digitoxin group and 177 (29.5%) in the placebo group (HR 0.86; 95% CI: 0.69 to 1.07) (37).

Agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors

A huge range of HFrEF patients are troubled with obesity as well, which accelerates the progression of HF (38). The long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, Tirzepatide, is a widely used weight-loss intervention. However, clinical data concerning its effects on cardiovascular outcomes were absent. The SUMMIT trial randomly assigned 731 patients with HFrEF to receive tirzepatide or placebo for at least 52 weeks, and came to the conclusion that treatment with tirzepatide reduced the risk of cardiovascular death and worsening HF, and improved health status [assessed by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] in patients with HFrEF and obesity. Adjudicated cardiovascular death or a worsening HF event were 9.9% with tirzepatide and 15.3% with placebo (HR 0.62; 95% CI: 0.41–0.95; P=0.03). Worsening HF events were 8.0% versus 14.2% (HR 0.54; 95% CI: 0.34–0.85), while cardiovascular death was infrequent in both groups (2.2% vs. 1.4%; HR 1.58; 95% CI: 0.52–4.83). Mean KCCQ-CSS change at week 52 favored tirzepatide by 6.9 points (95% CI: 3.3–10.6; P<0.001) (39). Results from the trial offered another option for the treatment of patients bothered by both HFrEF and obesity.

Novel metabolic accelerator

Excess body fat also plays a crucial role in the pathogenesis of HFpEF. HU6, a controlled metabolic accelerator designed to increase mitochondrial uncoupling, was evaluated in HuMAIN-HFpEF. To assess the efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO2) and body composition among patients with obesity-related HFpEF, the HuMAIN-HFpEF trial randomized 66 participants to HU6 and placebo. Compared with placebo, HU6 reduced body weight (between-group difference −2.86 kg; 95% CI: −4.68 to −1.04; P=0.003), total fat mass (−2.96 kg; 95% CI: −4.50 to −1.42; P<0.001), and visceral fat percentage (−1.3%; 95% CI: −2.1 to −0.5; P=0.003), without clear skeletal muscle loss, suggesting HU6 as a potential pharmacotherapy for obesity-related HFpEF (40). However, larger trials of longer duration are warranted to verify the conclusion of this clinical trial.

Intravenous ferric carboxymaltose

Among HF patients with iron deficiency, the efficacy of intravenous iron remained uncertain. The FAIR-HF2 DZHK05 trial recruited 1,105 patients with HF and iron deficiency to evaluate the efficacy and safety of ferric carboxymaltose. The first primary endpoint (cardiovascular death or first HF hospitalization) was lower with ferric carboxymaltose (HR 0.79; 95% CI: 0.63–0.99; P=0.04). Neither the second primary outcome (total HF hospitalizations) (264 vs. 320; rate ratio 0.80; 95% CI: 0.60–1.06; P=0.12) nor the third primary outcome (cardiovascular death or first HF hospitalization) (103 vs. 128; HR 0.79; 95% CI: 0.61–1.02; P=0.07) achieved statistical significance. Treatment with ferric carboxymaltose neither significantly reduced the time to first HF hospitalization or death from cardiovascular causes in the overall cohort or in patients with a transferrin saturation less than 20%, nor reduced the total number of HF hospitalizations vs. placebo, providing convincing evidence for the choice of treatment.

Cardiac myosin inhibition

Despite the rapid development of pharmacotherapy, few choices exist for the treatment of HFpEF with LVEF of 60% or greater. The EMBARK-HFpEF trial investigated the impact of the cardiac myosin inhibitor, mavacamten, in this patient population. The primary efficacy endpoints, assessed as the change from baseline to week 26, included NT-proBNP and high-sensitivity troponin T (hsTnT), while safety was monitored through treatment-emergent adverse events and potential LVEF reductions (<30%). Among the 30 patients enrolled, mavacamten was associated with reductions in NT-proBNP (−26%; 95% CI: −44 to −4; P=0.04), hsTnT (−13%; 95% CI: −23 to −3; P=0.02), and hsTnI (−20%; 95% CI: −32 to −6; P=0.01), with values trending back toward baseline after drug withdrawal. NYHA class and diastolic-function markers improved in 41.7% of the participants, and mean LVEF declined modestly by 3.2 percentage points (95% CI: 1.1–5.4; P=0.005) (41). Mavacamten was found to be potentially safe and associated with reversible reductions in NTproBNP, hsTnT, and hsTnI over the 26-week treatment period in patients with LVEF of 60% or greater.

Surgery and device-based therapy

LVADs

For end-stage HF, heart transplantation (HTx) and mechanical circulatory support (MCS) remain core options, yet donor shortages and lifelong immunosuppression limit transplant availability. Recent improvements in fully magnetically levitated continuous-flow left ventricular assist devices (LVADs) have improved the 2-year survival rate for patients to 81.2%, which is comparable to HTx (42). The CH-VAD (BrioHealth Technologies, China) is a fully magnetically levitated design centrifugal-flow device. In China, the multicenter study (77 implants) reported 91.6% survival at both 6 and 12 months, with relatively low rates of major complications such as right HF, reoperation for bleeding, and driveline infection. These findings support CH-VAD as a promising long-term support strategy, pending confirmation in further large-scale studies.

Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT)

ICDs are effective therapy for patients with HFrEF to prevent sudden cardiac death. However, the most common causes of death may change over time in HFrEF, which may influence the long-term risk-benefit balance of ICD implantation. An extended follow-up analysis of DANISH demonstrated that during a median follow-up of 13.2 years (Q1–Q3: 11.6–14.6 years), 294 patients (52.9%) in the ICD group and 299 (53.4%) in the control group died. Compared with usual clinical care, ICD implantation failed to reduce the incidence of all-cause death (HR: 0.96; 95% CI: 0.82–1.13), but it did reduce the occurrence of sudden cardiovascular death (HR: 0.54; 95% CI: 0.36–0.80) (43). The results from the analysis verified the long-term benefit of primary prevention ICD implantation in the reduction of sudden cardiovascular death.

The BUDAPEST-CRT Upgrade trial focused on the comparison between treatment with pacemaker/ICD alone and receiving CRT upgrade. Among the 360 HFrEF patients with pacemaker or ICD and ≥20% RV pacing burden assigned (3:2) to cardiac resynchronization therapy with defibrillator (CRT-D) upgrade or ICD, CRT-D upgrade improved NYHA class (adjusted OR 0.50; 95% CI: 0.32–0.80; P=0.003), produced greater NT-proBNP reduction (adjusted difference −1,257 pg/mL; 95% CI: −2,287 to −228; P=0.02), and attenuated age-related quality-of-life decline (EQ-5D-3L interaction P=0.003) (44). These results support CRT upgrade in appropriately selected paced HFrEF patients.

Another clinical trial, the CONSYST-CRT trial, addressed the absence of reliable comparison between conduction system pacing (CSP) and biventricular pacing (BiVP). A total of 134 patients with CRT indications were randomized and monitored for 12 months. The primary combined endpoint was all-cause mortality, cardiac transplantation, HF hospitalization, or LVEF improvement <5 points at 12-month follow-up. CSP met noninferiority for the primary composite endpoint (23.9% vs. 29.8%, respectively; mean difference −5.9; 95% CI: −21.1 to 9.2; P=0.02), and for several secondary domains, including the composite of mortality/transplant/HF hospitalization [11.9% vs. 17.9%; P<0.01 non-inferiority (NI)], echocardiographic response (66.6% vs. 59.7%; P=0.03 NI), NYHA class (P<0.001 NI), and QRS shortening (P<0.01). Although the absolute changes in LVEF (14.1%±10% vs. 14.4%±10%), LVESV (−27.9%±27% vs. −27.9%±28%), and septal flash (−2.2±2.7 mm vs. −2.7±2.4 mm) were comparable between the groups, noninferiority was not met (45). These findings support the potential of CSP as an alternative to BiVP.

Although conventional BiVP-CRT is effective overall, nonresponders remain at elevated risk of hospitalization and death (46). Therefore, the MORE-CRT MPP trial focused on the association between CRT with multipoint pacing (MPP) and improved clinical outcomes in this subgroup. After randomization of 3,724 non-responders to BIVP or MPP and approximately 6 months of follow-up, the secondary-analysis endpoint of HF hospitalization or all-cause death was lower with MPP than with BiVP [6.64% (48/722) vs. 10.44% (73/699); relative risk reduction 36%; P=0.01]. At multivariable analysis, MPP was associated with a lower occurrence of the main endpoint (odds ratio =0.60, P=0.0124) (47). These findings confirm that MPP was associated with a significant reduction of all-cause mortality and HF hospitalizations in prior non-responders to conventional BiVP.

Novel devices

preCARDIA

Novel devices aiming at the treatment of patients with acute decompensated heart failure (ADHF), preCARDIA, completed their early feasibility study in 2025. The preCARDIA system includes a proprietary superior vena cava (SVC) balloon that delivers programmed intermittent occlusion of the SVC. The VENUS-HF study involving 60 patients with ADHF investigated the safety and technical feasibility of preCARDIA and came to the conclusion that the use of the preCARDIA system was feasible and well tolerated, with exploratory signals of lower cardiac filling pressures and increased urine output. No significant difference in major adverse events was observed in the original (n=0/30) and newest (n=1/30) generation preCARDIA devices. In participants treated for 24±3 hours (n=52), right atrial pressure decreased by 23% (18±6 vs. 11±6 mmHg, P<0.001) and pulmonary capillary wedge pressure by 18% (30±8 vs. 24±9 mmHg, P<0.001) from baseline, while net urine output increased significantly compared with the preceding 24-hour period (−1.5±0.9 vs. −3.4±2.4 L, P<0.001) (48). These findings laid a solid foundation for larger, prospective studies, such as the upcoming COR-ADHF (Cardiovascular Unloading with preCARDIA in ADHF) trial, to further verify the clinical efficacy of preCARDIA.

Cardiac contractility modulation with defibrillation (CCM-D)

The CCM-D system combines cardiac contractility modulation with defibrillation capability for symptomatic Stage C/D HFrEF patients (LVEF ≤40%) who are not candidates for CRT. The phase results of the INTEGRA-D trial revealed that among 300 stage C/D HF patients with EF ≤40% and Class I/II ICD indication, 100% of patients were successfully defibrillated with CCM-D (P<0.001), with no inappropriate cardiac contractility modulation (CCM)/ICD interaction occurring despite hybridized circuits. The trial is still in progress with the objective of evaluating device-related complications and appropriateness of arrhythmia treatment through 6-month follow-up.

C-MIC

Although GDMT improves the clinical outcomes of patients with HFrEF, the recovery of myocardial function is hard to achieve, leaving high residual risk with worsening symptoms. The C-MIC device was subsequently designed to ameliorate myocardial oedema and left ventricular dysfunction. The C-MIC II trial was conducted to evaluate the safety and efficacy of C-MIC, recruiting 70 ambulatory patients with non-ischaemic dilated cardiomyopathy with LVEF of 25% to 35% and NYHA class III–IV. Participants were randomized to C-MIC or control group in addition to GDMT. At 6 months, C-MIC improved LVEF (mean difference 5.1%; 95% CI: 3.1–7.1; P<0.001) and yielded higher rates of clinically meaningful improvement in NYHA class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and 6-minute walk distance. Findings of the research indicate C-MIC as a potential treatment for patients with non-ischaemic chronic HFrEF.

Other clinical interventions

Influenza vaccination

Patients with HF are susceptible to infectious diseases, which may be responsible for their clinical deterioration (49). Influenza vaccination is widely used to prevent serious illness in vulnerable people, including those with HF. However, limited evidence supports this practice in patients with HF. The PANDA II trial randomly assigned 7,771 participants to influenza vaccination group and the usual care (control) group. The 12-month composite incidence of all-cause death or any readmission was significantly lower in the vaccination group compared to the usual care group [41.2% (1,378/3,342) vs. 47.0% (1,843/3,919); OR 0.83; 95% CI: 0.72–0.97; P=0.02]. The occurrence of serious adverse events was also reduced (52.5% vs. 59.0%; OR 0.82; 95% CI: 0.70–0.96; P=0.01). These findings demonstrate that influenza vaccination in patients with acute HF is able to improve survival and reduce the risk of readmission to hospital over the subsequent 12 months, suggesting the integration of influenza vaccination into inpatient care for an underserved high-risk patient group (50).

Fluid restriction

Fluid restriction is frequently recommended to patients with chronic HF, but solid evidence supporting such practice is in absence. Prior studies have not demonstrated any clear beneficial effect on either HF hospitalizations or mortality (51). By contrast, the negative effect of fluid restriction on patients’ life quality is solid (52-54). Hence, the FRESH-UP study was designed to evaluate the effects of a liberal versus a restrictive fluid regimen in patients with chronic HF. 504 patients were randomly assigned to liberal fluid intake or fluid restriction up to 1,500 mL per day. The primary endpoint was health status after 3 months, as assessed by the KCCQ-OSS. Secondary outcomes included thirst distress and safety events. At 3 months, adjusted KCCQ-OSS difference was 2.17 points (95% CI: −0.06 to 4.39; P=0.06), indicating that the primary endpoint was not met. Safety outcomes were similar, while thirst distress was greater in the restrictive group. These findings raise doubt on the benefit of fluid restriction in patients with chronic HF.

Rapid guideline-recommended medical therapy (GRMT) implementation

Rapid initiation and up-titration of GRMT are recommended for the treatment of HFrEF. However, scarce evidence supports its feasibility in daily practice. Therefore, the TITRATE-HF study was designed to evaluate the feasibility of rapid GRMT implementation in de novo HFrEF patients. One thousand five hundred eight participants with de novo HFrEF were enrolled. Within 6 weeks post-HFrEF diagnosis, 50% of the patients were initiated on quadruple therapy, with 84% maintaining this regimen at the 180-day follow-up. By 6 months, 66.3% were prescribed quadruple therapy, yet only 1.3% reached target doses across all classes. Although intolerance explained 20–37% of under-titration, physician acceptance of suboptimal dosing was also common. Importantly, rechallenging these drugs after discontinuation succeeded in over 83% of patients (55). These findings demonstrate that in real-world clinical practice, rapid initiation of GRMT for patients with HFrEF is feasible.

Initiation of therapy in suspected HF

Patients with suspected HF frequently experience delayed diagnostic echocardiography and initiation of therapy, which may contribute to preventable early adverse outcomes (56). To explore solutions, a cohort study was performed to estimate the potential benefit of the early initiation of an SGLT2i and/or MRA in patients with suspected HF and a pre-existing non-HF-related indication for treatment. Patients without a history of HF and who were not prescribed an SGLT2i or MRA were followed up for 12 months following a community-measured NT-proBNP ≥400 pg/mL. Among 74,945 participants, 24,082 received an HF diagnosis within 12 months (64% outpatient, 36% during HF hospitalization). It was estimated that initiating both therapies at the measurement of elevated NT-proBNP could prevent HF hospitalization or death in approximately 84 per 1,000 treated patients over 1 year (57). Findings from this study provide solid evidence for the early initiation of an SGLT2i and an MRA in patients with suspected HF and elevated NT-proBNP, indicating a simple clinical strategy with potentially large public health benefits.

Emerging therapies

Stem cell therapy has emerged as a promising intervention because it can support repair of cardiac tissue and preserve ventricular function.

A recent study put forward a hypothesis that epicardial engineered heart muscle (EHM) allografts, synthesized from iPSC-derived cardiomyocytes and stromal cells, can facilitate both structural and functional remuscularization of the failing heart without significant side effects. In a rhesus macaque model, EHM grafts demonstrated long-term retention (up to 6 months) and a dose-dependent enhancement of the target ventricular wall in both healthy and infarcted hearts. In HF models, elevation in target-wall contractility and ejection fraction was observed, with imaging and histopathology supporting vascularized graft integration without the occurrence of arrhythmia or tumour growth (58). These thrilling findings provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair.

Prospect

In 2025, multiple ongoing studies concerning HF treatment have displayed inspiring prospects. The INNOVATE trial on the novel LVAD, BrioVAD, has fulfilled its safety phase and entered the pivotal phase, highlighting that China’s high-end medical devices have broken through the world’s highest regulatory barriers with innovative technology. CorVad, the first percutaneous ventricular assist device (pVAD) approved by the Chinese National Medical Products Administration for sale in 2025, offers more options for the treatment of HF patients.

Substantial large-scale clinical trials launched in 2025 have brought new vitality to the treatment of HF. The STRIVE study aims to evaluate whether high-frequency QRS (HF-QRS) signal parameters and circulating myocardial fibrosis biomarkers (such as PIIINP, Galectin-3, and sST2) can improve risk stratification in patients with chronic HF. The HEARTFELT trial aims to establish if the Heartfelt device is safe to use and effective at reducing HF hospitalization. The DANUTRIO-HF trial investigates whether these supplements can make a difference for individuals with HF. The BRANCH-HF study aims to learn the safety and effects of the study medicine (PF-07328948) for the possible treatment of HF. The Prevent-HF trial aims to evaluate the effect of Baxdrostat in combination with Dapagliflozin compared with Dapagliflozin alone on the risk of incident HF and cardiovascular death. The SELEQT-HF [SELEnium and coenzyme Q10 (CoQ10) NuTrition for HF] study evaluates the effect of adding Selenium and CoQ10 on top of standard HF therapy in patients with HF. The BRIGHTEN-HF trial assesses the impact of CCM on mortality and HF hospitalizations in Medicare-eligible patients with HF who meet indications for CCM. The SYNCHRONICITY trial compares the safety and effectiveness of left bundle branch area pacing and conventional CRT in HF. A new cohort study aims to assess the comparative effectiveness of tirzepatide versus semaglutide with respect to cardiovascular events in patients with type 2 diabetes and HF with preserved ejection fraction. The ICONIC-HF trial evaluates if the intravenous (IV) iron treatment ferric derisomaltose helps in the treatment of chronic HF in people with iron deficiency. The MARITIME-HF trial aims to examine if maridebart cafraglutide as an adjunct to standard of care will lead to a reduction in HF events in participants with HFpEF or HFmrEF who are obese. The ELEVATE-HFpEF evaluates the safety and efficacy of dual chamber personalized pacing compared to minimal or no pacing for the treatment of patients with HFpEF. The CARVTOP-ICD trial evaluates the impact of carvedilol versus metoprolol succinate in patients with HFrEF and an ICD. The DUP-TIRZSEMA trial assesses the comparative effectiveness of tirzepatide vs. semaglutide after emulating the pivotal RCTs of each drug used to support regulatory approval in HFpEF (SUMMIT and STEP-HFpEF DM trials). Upcoming results from these trials are expected to further improve the treatment of HF and the prognosis of patients (Table 2).

As the therapeutic landscape continuously evolves with the emergence of state-of-the-art therapies, HF management is shifting from standardized protocols toward a paradigm of precision medicine. With regard to pharmacotherapy, results from the FINE-HEART trial are anticipated to solidify the role of finerenone across the entire LVEF spectrum, potentially elevating the class of recommendation for MRAs. Similarly, the SUMMIT trial is poised to establish tirzepatide as a transformative therapy for obesity-related HFpEF, shifting the clinical focus from symptoms to underlying metabolic drivers. Meanwhile, the VICTOR trial aims to expand the therapeutic window for vericiguat by evaluating its efficacy in a broader HFrEF population, which may integrate soluble guanylate cyclase (sGC) stimulators deeply into the standard therapy. Parallel to pharmacological advances, the evolution of medical devices, such as preCARDIA, CCM-D, and C-MIC, has provided crucial supplementary options when pharmacotherapy proves insufficient, thereby significantly improving the prognosis of patients with advanced HF.

Driven by technological advancements and deepening clinical insights, therapeutic perspectives are evolving rapidly. Regenerative medicine, particularly stem cell therapy, holds significant promise in HF treatment, as evidenced by various exploratory studies evaluating its efficacy and safety. While challenges regarding long-term safety and large-scale manufacturing persist, these innovations may herald a potential shift in HF management. Similarly, artificial intelligence (AI) is changing the landscape through trials like HEARTFELT and STRIVE, which focus on AI-driven diagnostics and predictive modeling. Rather than replacing clinical judgment, AI is poised to refine risk stratification and facilitate the identification of the optimal therapeutic window before clinical decompensation. As AI technology matures, it may increasingly serve as an assistant in deciding therapeutic strategies.

Conclusions

The year 2025 witnessed a rapid revolution in HF management. The successful application especially finerenone in HFpEF/HFmrEF and tirzepatide in obese HFrEF has encouraged further exploration in pharmacotherapy. The progress in device therapy such as the preCARDIA system has offered brand-new insights and options for the treatment of HF. The emergence of breakthroughs in cardiac xenotransplantation also demonstrated a promising solution to the shortage of donor hearts. Emerging frontier treatments like stem cell therapy are thrilling as they have broadened our imagination of HF treatment. The paradigm is conclusively moving from conventional neurohormonal inhibition to dynamic, phenotype-specific, personalized management.

Despite the inspiring advances, the rising global burden and persistent hospitalization rates still highlight the ongoing challenge. Confronted with these circumstances, more large-scale research is in urgent need to further update the treatment of HF with the expectation of improving the long-term prognosis and discovering new therapies to address complex and severe HF subtypes.

Acknowledgments

The authors would like to thank the colleagues from the department of cardiology in Zhongshan Hospital for their assistance in completing the manuscript. We also thank the peer reviewers for their constructive feedback which helped improve the quality of this review.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0188/prf

Funding: This work was supported by Innovation Fund for Industry-university Research of Chinese Universities (No. 2024JC012), National Key Research and Development Program of China (Nos. 2023YFC3606500, 2023YFC2506500), Special Clinical Research Project of Shanghai, Municipal Health Commission (No. 20244Y0022), and Shanghai “Rising Stars of Medical Talent” Youth Development Program [No. SHWSRS (2024)_070].

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0188/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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