Heart failure is a serious condition where the heart cannot pump blood effectively. Some patients with severe heart failure (known as heart failure with reduced ejection fraction, or HFrEF) can experience significant improvement in their heart function after receiving guideline-directed medical therapy. This phenomenon is called heart failure with improved ejection fraction (HFimpEF). However, it is not fully understood why some patients improve while others do not.

This study aims to explore the molecular mechanisms behind this improvement by collecting blood samples and clinical data from patients with HFrEF in China. Participants will be followed for 12 months, and their heart function will be assessed at multiple time points. By analyzing blood biomarkers and imaging data, researchers hope to identify predictors of heart function improvement and develop a model to help personalize treatment for heart failure patients.

This is an observational study, meaning participants will receive their usual medical care and no experimental treatments or medications will be given. The study involves regular clinical visits and blood draws as part of routine care.

Inclusion Criteria:

1. Age ≥ 18 and ≤ 90 years at the time of signing informed consent.

2. Diagnosed with symptomatic chronic heart failure with reduced ejection fraction (NYHA class II-IV) and has been on stable, optimized guideline-directed medical therapy and/or device therapy for at least 4 weeks.

3. Left ventricular ejection fraction ≤ 40% assessed by echocardiography or cardiac MRI within 1 month prior to enrollment.

   1. For patients who have undergone coronary revascularization (PCI or CABG), valve repair/replacement, cardiac resynchronization therapy (CRT), or other treatments that may improve LVEF (e.g., initiation of beta-blockers), LVEF must be reassessed at least 1 month after the intervention before enrollment.
   2. If multiple LVEF measurements are available, the most recent one will be used for eligibility determination.

4. NT-proBNP level measured at enrollment meeting at least one of the following criteria:

   1. For LVEF 36%-40%: NT-proBNP ≥ 2500 pg/mL (sinus rhythm) or ≥ 5000 pg/mL (atrial fibrillation).
   2. For LVEF 31%-35%: NT-proBNP ≥ 1000 pg/mL (sinus rhythm) or ≥ 2000 pg/mL (atrial fibrillation).
   3. For LVEF ≤ 30%: NT-proBNP ≥ 600 pg/mL (sinus rhythm) or ≥ 1200 pg/mL (atrial fibrillation).
   4. For patients rehospitalized for heart failure (LVEF ≤ 40% with heart failure hospitalization within the past 12 months): NT-proBNP ≥ 600 pg/mL (sinus rhythm) or ≥ 1200 pg/mL (atrial fibrillation).

5. Receiving standard HFrEF medical therapy, unless contraindicated or intolerant, and stable for at least 4 weeks (excluding diuretic dose adjustments). The regimen should include, if applicable: ACE inhibitor, ARB, or sacubitril/valsartan (ARNI) + beta-blocker + mineralocorticoid receptor antagonist (MRA) + SGLT2 inhibitor. Other agents such as vericiguat may be used with documentation.

6. Estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m² (CKD-EPI) at enrollment.

7. Willing and able to provide signed informed consent and comply with the requirements of the protocol.

Exclusion Criteria:

1. Poor treatment adherence that may lead to worsening heart failure symptoms and signs due to non-compliance with prescribed medication.

2. Systolic blood pressure < 90 mmHg at enrollment or symptomatic hypotension within the past 24 hours.

3. Myocardial infarction (defined by elevated cardiac enzymes with ischemic symptoms or new ischemic ECG changes), unstable angina, stroke, or transient ischemic attack (TIA) within 90 days prior to enrollment.

4. Coronary revascularization (PCI/CABG) or valve repair/replacement within 1 month prior to enrollment, or planned to undergo such procedures after enrollment.

5. CRT implantation within 1 month prior to enrollment, or planned CRT implantation during the study period.

6. Prior heart transplantation or ventricular assist device (VAD) implantation, or planned VAD implantation during the study period.

7. History of specific cardiomyopathies, including restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic obstructive cardiomyopathy, infiltrative cardiomyopathy (including but not limited to amyloidosis), familial or genetic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy.

8. Complex congenital heart disease or severe uncorrected primary valvular heart disease.

9. Symptomatic bradycardia or second/third-degree atrioventricular block without a pacemaker.

10. Life expectancy < 1 year due to non-cardiovascular causes (including but not limited to malignant tumors).

11. Active malignancy or history of malignancy diagnosed within 2 years prior to screening, except for: (a) adequately treated basal cell carcinoma of the skin; (b) carcinoma in situ of the cervix; (c) low-risk prostate cancer (defined as PSA < 10 ng/mL, Gleason score ≤ 6, and clinical stage T1c or T2a prior to treatment).

12. Alternative or concomitant diagnoses that could explain the participant's heart failure symptoms and signs (e.g., severe anemia, hypothyroidism, nephrotic syndrome).

13. Primary pulmonary hypertension, chronic pulmonary embolism, or severe pulmonary disease (including COPD requiring home oxygen or frequent hospitalizations, or COPD exacerbation requiring invasive mechanical ventilation within 12 months prior to enrollment).

14. Hepatic impairment: total bilirubin ≥ 1.5 × upper limit of normal (ULN), or ALT/AST ≥ 3 × ULN (patients with Gilbert's syndrome and unconjugated hyperbilirubinemia with total bilirubin ≥ 1.5 × ULN but without other evidence of hepatic impairment may be enrolled).

15. Known blood-borne infectious diseases.

16. Severe or unstable kidney disease: eGFR < 20 mL/min/1.73 m² (CKD-EPI) at randomization, rapidly deteriorating renal function, or requiring renal replacement therapy.

17. Systolic blood pressure ≥ 160 mmHg (if on < 3 antihypertensive agents) or ≥ 180 mmHg (regardless of treatment) at enrollment.

18. Hemoglobin level < 9 g/dL.

19. Major surgery (as judged by the investigator) within 90 days prior to enrollment, or planned major elective surgery within 90 days after screening.

20. Paroxysmal or permanent atrial fibrillation excluded only if:

    1. Requiring cardioversion (e.g., electrical cardioversion, atrial fibrillation ablation, or antiarrhythmic therapy) within ≤ 3 months prior to screening.
    2. Heart rate not adequately controlled with anticoagulation therapy for at least 3 months prior to screening.

21. Participation in another clinical trial and use of an investigational drug within 1 month prior to enrollment.

22. Any other clinically significant disease, malignancy, active infection, condition, or disorder that, in the opinion of the investigator or medical monitor, may pose a safety risk to the participant or interfere with the evaluation, procedures, or completion of the study.

This study will enroll adult patients (≥18 to ≤90 years of age) with symptomatic chronic heart failure with reduced ejection fraction (HFrEF), defined as NYHA class II-IV and left ventricular ejection fraction ≤40% within 1 month prior to enrollment. Participants must be on stable, optimized guideline-directed medical therapy for at least 4 weeks and meet specified NT-proBNP thresholds. Patients will be recruited from the cardiology departments and outpatient clinics of participating heart failure centers across China. Individuals with poor adherence, severe comorbidities, or other conditions that may interfere with study procedures or pose safety risks will be excluded.