The EPIC-HFpEF registry is a nationwide Italian study that follows people with a specific type of heart failure called HFpEF. About 500 patients will be enrolled from several specialized hospitals and monitored for up to two years, without changing their usual treatment.

The goal is to better understand this complex condition by identifying different patient "types" based on clinical features, heart imaging, and blood markers. Researchers will also look at how these groups are treated in real life and how their disease progresses over time.

By doing this, the study aims to improve how doctors classify and manage HFpEF, moving toward more personalized and effective care for patients in the future.

Study Design: A multicenter, national, non-randomized observational study with both retrospective and prospective components, conducted at approximately 10 Italian tertiary centers specializing in the management of heart failure.The registry consecutively will enroll adult patients diagnosed with HFpEF, including both inpatients and outpatients, and includes follow-up for up to 24 months or until death or withdrawal of consent. No intervention aimed at modifying standard clinical practice is planned.

Study Purpose and Rationale: The rationale for the EPIC-HFpEF registry is to:

• describe the true prevalence of the different HFpEF phenotypes in clinical practice;
• characterize these phenotypes using an integrated approach that includes advanced echocardiography, clinical data, and biomarkers;
• provide the foundation for personalized medicine, tailored to the individual patient's pathophysiological profile.

Study Objectives:

Primary Objectives

• To identify distinct phenotypes of HFpEF based on clinical parameters, echocardiographic findings (standard and advanced), biomarkers, and comorbidities.
• To describe the prevalence and temporal evolution of the different HFpEF phenotypes in a real-world setting.

Secondary objectives

• Evaluate the implementation of guideline-recommended therapies (neurohormonal modulators, SGLT2 inhibitors, GLP-1 agonists) and the treatment of comorbidities across the different phenotypes.
• Analyze the associations between circulating biomarkers and structural and functional cardiac alterations.
• Study the impact of disease duration on clinical outcomes in relation to phenotype.
• Assess the cumulative risk of cardiovascular events and their prognostic value in the different subgroups of HFpEF.

Inclusion Criteria

• Age ≥ 18 years.
• Written informed consent.
• Diagnosis of chronic or acute heart failure with:o Left ventricular ejection fraction ≥ 50%;o Elevated natriuretic peptide levels (NT-proBNP ≥300 pg/mL in sinus rhythm or ≥600 pg/mL in atrial fibrillation); or Echocardiographic evidence of increased left ventricular filling pressures.
• NYHA Class II-IV.

The following are also included as comparison groups:

• Patients with recovered/improved EF (previous EF <40%);
• Patients with mildly reduced EF (40-49%, HFmrEF).

Exclusion criteria

• Concurrent participation in interventional clinical trials.
• Life expectancy < 1 year due to non-cardiac causes.
• Recent infectious, inflammatory, autoimmune, or neoplastic diseases (≤6 months).
• Advanced chronic kidney disease (eGFR <15 ml/min/1.73 m²).
• Recent major cardiovascular events (MI, stroke, cardiac surgery within the last 3 months).
• Severe pulmonary diseases, congenital heart disease, primary pulmonary hypertension.
• Moderate-to-severe degenerative valvular disease, specific or constrictive cardiomyopathies.
• Recent implantation of an ICD or cardiac resynchronization therapy.

Study Duration

• Enrollment period: 12 months.
• Follow-up for each patient: up to 24 months.
• Total study duration: approximately 3 years.

Scheduled visits include:

• baseline (T1),
• 6-month follow-up (T2),
• 12-month follow-up (T3),
• additional clinical follow-up for up to 24 months to collect event data.

Sample Size We plan to enroll approximately 500 patients with HFpEF, assuming an average of 50 patients per participating center.This sample size is considered adequate for identifying phenotypic clusters and estimating their prevalence in the real-world population of patients with HFpEF.ConclusionThe EPIC-HFpEF registry aims to improve understanding of the clinical and pathophysiological complexity of HFpEF by identifying phenotypes that are prognostically relevant and potentially responsive to targeted therapeutic strategies, with direct implications for clinical practice and the design of future interventional studies.

Inclusion Criteria:

• Patients ≥ 18 years old
• Signed patient informed consent form (ICF)
• Diagnosis of chronic (documented HF hospitalization in the last year) or acute decompensated HF shown by signs and symptoms of HF and LVEF >50% and, according to guidelines and the universal definition of HF, elevated levels of natriuretic peptides (NT-proBNP ≥300 pg/ml in sinus rhythm or NTproBNP ≥600 pg/ml in atrial fibrillation), at the time of enrolment (10)
• Echocardiographic evidence of increased estimated LV filling pressures according to current guidelines

Exclusion Criteria:

• Planned participation or participation in a clinical trial;
• Life expectancy < 1 year because of non-cardiac causes;
• History of recent (6 months) infective, or inflammatory, autoimmune or neoplastic diseases.
• Stage >4 CKD (estimated glomerular filtration rate [eGFR] < 15 ml/min/1.73m2),
• Myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischemia or newly developed ischemic ECG changes), coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or TIA in past 3 months;
• Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalization for exacerbation within 12 months;
• Congenital heart disease.
• Primary pulmonary hypertension
• Moderate-to-severe degenerative (primary) valve disease
• Cardiomyopathy based on muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), or known pericardial constriction;
• Implantation of cardioverter defibrillator (ICD) within 3 months
• Implanted cardiac resynchronization therapy (CRT) and/or stable RV pacing.

The study population will consist of consecutive patients with HF (NYHA class II - IV), aged 18 years or older, able to give their written informed consent to participate to the registry. Each patient will be uniquely identified in the study by a combination of his/her site number and patient number. No name will be entered in the database.

Once obtained approval from each Ethics Committee center, consecutive patients will be included, up to the achievement of the study size. Patients may also be enrolled retrospectively, provided they give their written informed consent during a follow-up visit. Enrollment will be performed during outpatient visits or at-discharge in patients hospitalized for HF. Outpatient's visits will be further classified as planned or unplanned visits for worsening HF symptoms.

Patient data collected during the study will include demographics, medical history, vital signs, LVEF and main cardiac structure and function parameters, and laboratory assessments.