To assess the impact of PADN combined with guideline-directed medical therapy (GDMT) versus a sham procedure with GDMT on clinical outcomes in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF>40%). Outcomes include cardiovascular death, HF-related rehospitalization, requirement for heart transplantation or need of valvular treatment or LVAD or pacemaker implantation, and worsening in outpatients (defined as requirement for intravenous therapy or diuretic intensification, including increasing the types or dose of diuretics).

A randomized, multicenter, blinded, sham-controlled trial in

Subjects with chronic HFpEF (LVEF >40%) meeting inclusion criteria and no exclusion criterion will be enrolled from 25 + centers in China within 24 months. Patients will be randomized 1:1 to:

• Experimental Group: PADN + GDMT
• Control Group: Sham procedure + GDMT

GDMT regimen: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) + Spironolactone. SGLT2i can be dapagliflozin or empagliflozin.

• Dapagliflozin: Target maintenance dose 10 mg/day. Contraindicated if eGFR persistently <25 mL/min/1.73 m².
• Empagliflozin: Target maintenance dose 10 mg/day. Contraindicated if eGFR persistently <20 mL/min/1.73 m².
• Spironolactone: Starting dose 10-20 mg/day, maximum dose 40 mg/day. Suspend if serum potassium is >5.5 mmol/L; restart at half dose after correction. Permanently discontinue if serum potassium is >6.0 mmol/L. Suspend and evaluate if eGFR persistently declines >30% or <30 mL/min/1.73 m².

Other medications are left at the physician's discretion. The proportion of patients with persistent atrial fibrillation is not to exceed 35%.

Inclusion Criteria:

1. The subject, or their legal guardian, must have a clear understanding of the trial's design and treatment procedures. They must provide written informed consent before any trial-specific tests or procedures are conducted.

2. Both male and female subjects age between 18 ~ 85 years old. 3. Dyspnea on exertion (NYHA functional class II-IV) not explained by non-cardiac or ischemic etiology.

4. LVEF >40% on imaging within 24 months prior to enrollment, with no clinical changes suggesting worsening systolic function.

5. Elevated NT-proBNP or BNP levels meeting the following thresholds stratified by age and atrial fibrillation (AF) status:

1. Patients WITHOUT atrial fibrillation:

   1. Age <50 years: BNP >100 pg/mL or NT-proBNP >450 pg/mL
   2. Age 50-75 years: BNP >150 pg/mL or NT-proBNP >900 pg/mL
   3. Age >75 years: BNP >200 pg/mL or NT-proBNP >1800 pg/mL

2. Patients WITH atrial fibrillation:

   1. BNP >150 pg/mL or NT-proBNP >300 pg/mL

      6. Stable HF GDMT (no change in either types or dose) for ≥14 days prior to enrollment, including SGLT2i and spironolactone. Other medication, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitor (ARNI, sacubitril/valsartan), beta-blockers, or calcium channel blockers (CCBs), were left at physician's discretion.

      7. Dose changes of ACEIs, ARBs, sacubitril/valsartan, beta-blockers, or CCBs did not exceed 100% of baseline dose (i.e., no doubling or halving).

      8. Continuous diuretic use for ≥14 days prior to screening, with stable dose in the last 7 days.

      9. Meet at least one of the following:

   1. Hospitalization for decompensated HF within the past 12 months
   2. Received intravenous loop diuretic or ultrafiltration for HF within the past 12 months
   3. Documented resting pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) >15 mmHg, or exercise PCWP ≥25 mmHg, or exercise LVEDP ≥20 mmHg on right heart catheterization within the past 12 months
   4. Echocardiographic evidence within the past 24 months of left atrial enlargement (LA anterior-posterior diameter male >40 mm, female >38 mm; LA area ≥20 cm², LA volume index ≥29 ml/m²) or left ventricular hypertrophy (interventricular septal thickness or LV posterior wall thickness ≥12 mm).

Exclusion Criteria:

1. Hospitalization for HF within 7 days prior to screening.
2. Participation in an interventional trial (using investigational drug or device) of a non-observational registry study within 14 days prior to screening.
3. History of blood or bone marrow donation within 4 weeks prior to screening, or planned donation during the study.
4. Implantation of pulmonary artery pressure monitor or pacemaker within 4 weeks prior to screening, or planned implantation during the study.
5. Hospitalization within 30 days prior to screening for: acute ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), unstable angina, percutaneous coronary intervention (PCI), or cardiac surgery.
6. Cardiac resynchronization therapy (CRT) within 90 days prior to screening.
7. Planned revascularization (PCI or CABG), major cardiac surgery (including coronary artery bypass grafting, valve replacement, ventricular assist device implantation, heart transplantation, other surgery requiring thoracotomy), transcatheter aortic valve replacement (TAVR), or CRT implantation within 90 days after screening.
8. History of femoral or jugular vein surgery.
9. Life expectancy <1 year at screening.
10. Estimated glomerular filtration rate (eGFR) <20 ml/min/1.73 m² at screening (calculated using the modified MDRD formula).
11. BNP <150 pg/ml and NT-proBNP <300 pg/ml at screening.
12. Serum potassium >5.5 mmol/L at screening.
13. Physical examination showing volume depletion at screening or randomization.
14. Mean supine systolic blood pressure <100 mmHg at screening or randomization.
15. Uncontrolled hypertension, defined as mean supine systolic blood pressure ≥160 mmHg (average of three measurements) at screening.
16. Documented stable-state LVEF <40% within the past 24 months.
17. Current active malignancy (excluding non-melanoma skin cancer).
18. HF due to specific cardiomyopathies, including: restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe valvular stenosis, hypertrophic obstructive cardiomyopathy (HOCM).
19. Chronic obstructive pulmonary disease (COPD) judged as the primary cause of dyspnea.
20. Myocardial ischemia judged as the primary cause of dyspnea.
21. Isolated right heart failure due to pulmonary disease.
22. Complex congenital heart disease.
23. History of allergic reaction to guideline-directed HF medications.
24. Pregnant/lactating women. Women of childbearing potential (WOCBP) defined as post-menarche and not permanently sterilized (hysterectomy/bilateral tubal ligation) or postmenopausal (natural amenorrhea ≥12 months without other medical cause). Sexually active WOCBP must agree to use medically accepted contraception during the study, including: |surgical sterilization, progestin contraceptives (oral/implant), barrier methods (condom/diaphragm) with spermicide, intrauterine device (IUD). Urine pregnancy test required at each visit; negative result required for continued participation.
25. Other exclusion criteria as judged by the investigator, including but not limited to conditions that may jeopardize patient safety during study participation, factors interfering with study data interpretation, or patients unlikely to comply with study procedures/requirements.

DATA sharing could be accepted upon other researchers reached out to the PI of this trial, with approval.

It will be available after 6 months since publication of this trial, unless PI agreed earlier.

upon approval by PI of this trial

Staff from the core laboratories