Heart failure with reduced ejection fraction (HFrEF) is associated with impaired exercise capacity and abnormal exercise hemodynamics despite contemporary guideline-directed medical therapy (GDMT). Vericiguat, a soluble guanylate cyclase stimulator, has demonstrated clinical benefits in selected patients with HFrEF, but its effects on exercise physiology remain incompletely understood.

The EVERHETT-HF study is a prospective observational cohort study designed to evaluate the effects of treatment with vericiguat on exercise capacity and invasive exercise hemodynamics in patients with stable HFrEF receiving maximally tolerated guideline-directed medical therapy (GDMT). Participants undergo comprehensive cardiopulmonary exercise testing (CPET) and exercise right heart catheterization (ERHC) to assess functional and hemodynamic responses during exercise.

Patients with chronic heart failure with reduced ejection fraction (HFrEF) frequently demonstrate persistent impairment in exercise tolerance and abnormal exercise hemodynamics despite contemporary guideline-directed medical therapy (GDMT). Although vericiguat has demonstrated clinical benefits in selected HFrEF populations, the physiological effects of soluble guanylate cyclase stimulation on exercise performance and invasive exercise hemodynamics remain incompletely characterized.

The EVERHETT-HF study is a prospective observational cohort study designed to evaluate the association of vericiguat therapy with changes in exercise capacity and invasive exercise hemodynamics in patients with stable HFrEF receiving maximally tolerated GDMT. Treatment decisions, including the initiation and dose titration of vericiguat, are made according to routine clinical practice and the judgment of the treating physician, independent of the study protocol.

Consecutive eligible adult patients with chronic HFrEF are prospectively enrolled and categorized into two cohorts according to the treatment prescribed by their treating physician: patients receiving guideline-directed medical therapy (GDMT) alone and patients receiving GDMT plus vericiguat. Clinical management is not influenced by study participation.

All participants undergo comprehensive baseline evaluation, including clinical assessment, laboratory testing, cardiopulmonary exercise testing (CPET), and exercise right heart catheterization (ERHC). Follow-up assessments are performed after approximately 12 months using the same standardized evaluation protocol.

Cardiopulmonary exercise testing is performed on a cycle ergometer using a symptom-limited incremental exercise protocol. Functional parameters include peak oxygen uptake (peak VO₂), percentage of predicted peak VO₂, ventilatory efficiency (VE/VCO₂ slope), oxygen uptake efficiency slope (OUES), peak oxygen pulse, anaerobic threshold, respiratory exchange ratio (RER), and exercise duration.

Exercise right heart catheterization is performed using a Swan-Ganz catheter with serial invasive hemodynamic measurements obtained at rest and during standardized supine bicycle exercise. Hemodynamic variables include right atrial pressure (RAP), pulmonary artery systolic, diastolic and mean pressures (sPAP, dPAP, and mPAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), cardiac index (CI), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), cardiac power output (CPO), cardiac power index (CPI), transpulmonary gradient (TPG), diastolic pressure gradient (DPG), pulmonary artery pulsatility index (PAPi), and other derived exercise hemodynamic indices.

The primary objective of the study is to evaluate the association of vericiguat therapy with longitudinal changes in exercise capacity and invasive exercise hemodynamics in patients with stable HFrEF. Secondary objectives include the assessment of additional cardiopulmonary exercise variables, invasive hemodynamic parameters, laboratory biomarkers, echocardiographic measurements, and overall functional status during follow-up.

This investigator-initiated study aims to provide detailed mechanistic insights into the relationship between vericiguat therapy and exercise physiology in patients with stable HFrEF under routine clinical practice through the combined use of cardiopulmonary exercise testing and invasive exercise hemodynamic assessment.

Inclusion Criteria:

Adults aged ≥18 years. Chronic heart failure with reduced ejection fraction (LVEF ≤40%). Stable chronic heart failure receiving maximally tolerated guideline-directed medical therapy (GDMT).

Clinically stable for at least 6 months prior to enrollment without hospitalization for worsening heart failure or major modification of heart failure therapy.

Able to perform symptom-limited cardiopulmonary exercise testing (CPET). Eligible to undergo exercise right heart catheterization (ERHC). Able to provide written informed consent.

Exclusion Criteria:

Acute decompensated heart failure. Recent hospitalization for worsening heart failure (<6 months). Systolic blood pressure <110 mmHg. Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m². Severe hepatic dysfunction. Severe anemia (hemoglobin <9 g/dL). Contraindication to right heart catheterization. Inability to perform CPET. Pregnancy or breastfeeding. Any condition judged by the treating physician to preclude safe participation.

The study population consisted of consecutive adult patients (≥18 years) with stable chronic heart failure with reduced ejection fraction (LVEF ≤40%) receiving maximally tolerated guideline-directed medical therapy (GDMT). Patients were clinically stable and underwent standardized cardiopulmonary exercise testing (CPET) and exercise right heart catheterization (ERHC) as part of their clinical evaluation at Alexandra General Hospital. Participants were prospectively enrolled and classified according to routine clinical treatment with GDMT alone or GDMT plus vericiguat.

Individual participant data (IPD) will not be shared because this is a single-center, investigator-initiated study with a small sample size, and no data-sharing plan has been established.