The goal of this clinical trial is to investigate how vericiguat benefits adults with stable heart failure with reduced ejection fraction (HFrEF) who are already receiving guideline-directed medical therapy.

The main questions are:

• Does vericiguat improve right ventricular systolic function, measured by tricuspid annular plane systolic excursion (TAPSE)?
• Does vericiguat favourably influence myocardial remodeling, fibrosis, angiogenesis, inflammation, metabolism, renal function, and hematologic balance?
• Do genetic and oxidative stress profiles modify treatment response? Researchers will compare a group receiving vericiguat plus usual care with a group receiving usual care alone to assess structural, functional, and biomarker changes over 12 months.

Participants will:

• Have blood drawn at baseline and follow-up visits for biomarker, metabolomic, genetic, transcriptomic, and hematologic analyses, including platelet function testing
• Perform oral glucose tolerance tests (OGTT) to assess insulin resistance
• Undergo echocardiography, cardiac magnetic resonance imaging, and cardiac scintigraphy to evaluate heart structure, function, and perfusion
• Attend follow-up visits at 1, 3, 6, and 12 months Open-label extension: After the 12-month randomized phase, participants originally assigned to usual care will be offered open-label vericiguat and followed for an additional 12 months. This exploratory extension will reassess study outcomes to evaluate the consistency and magnitude of response to vericiguat in the prior control cohort.

Heart failure with reduced ejection fraction (HFrEF) involves pathologic processes that lead to maladaptive remodeling of the myocardium with ventricular dilation, wall thickening, and cellular and microvascular changes that progressively worsen cardiac function. Many established therapies for heart failure can promote reverse remodeling, improving symptoms and long-term outcomes.

Vericiguat is a soluble guanylate cyclase (sGC) stimulator that increases cyclic guanosine monophosphate (cGMP), a signaling molecule with vasodilatory and cardioprotective effects that is impaired in heart failure. Randomized trials show that vericiguat reduces the risk of worsening heart-failure events in HFrEF after recent decompensation, and emerging evidence indicates that these benefits extend to stable HFrEF. The mechanisms by which vericiguat may benefit patients with HFrEF remain incompletely understood.

Preclinical data suggest that augmenting cGMP signaling may confer antifibrotic, antihypertrophic, antiinflammatory, proangiogenic, and metabolic effects. These mechanisms could contribute to reverse remodeling and improved clinical status, but they require confirmation in a clinical setting.

This randomized, controlled study will evaluate the effects of vericiguat on right ventricular systolic function, assessed by tricuspid annular plane systolic excursion (TAPSE), and will characterize associated structural and biologic changes in adults with stable HFrEF on contemporary GDMT. Sixty participants will be randomized to vericiguat plus usual care or to usual care alone and followed for 12 months, with study visits at 1, 3, 6, and 12 months.

At each visit, blood samples will be collected for analysis of circulating biomarkers reflecting fibrosis, inflammation, angiogenesis, renal function, and metabolism, as well as transcriptomic profiling. Comprehensive metabolomic profiling will be performed, and insulin resistance will be evaluated by oral glucose tolerance testing (OGTT) at baseline and 12 months. Hematologic parameters will be measured at each visit, while platelet function will be assessed at baseline and 12 months.

Cardiac structure and function will be assessed using transthoracic echocardiography, cardiac magnetic resonance imaging, and cardiac scintigraphy. Imaging will quantify biventricular volumes, systolic function, fibrosis, and perfusion.

The study will investigate whether cumulative oxidative stress and genetic variation modify the response to vericiguat. Cumulative oxidative stress will be quantified from serial 8-hydroxy-2'-deoxyguanosine (8-OHdG) measurements (area under the curve) and examined for interaction with treatment effects on TAPSE and other outcomes. Genetic analyses will assess variants in drug-disposition and NO-sGC-cGMP pathway genes for associations with response.

After completing the 12-month randomized phase, participants originally assigned to usual care will be offered open-label vericiguat and followed for an additional 12 months. This non-randomized, exploratory extension will re-measure the randomized-phase outcomes to evaluate the consistency and magnitude of response to vericiguat in the prior control cohort, using Month 12 values as the extension baseline.

Overall, this research is designed to clarify the pathophysiologic mechanisms of vericiguat therapy in HFrEF and to support more personalized treatment strategies for patients living with heart failure.

Inclusion Criteria:

• Written informed consent from an adult patient (≥ 18 years old) to participate in the clinical study,
• Stable HFrEF defined as no heart failure worsening in the 6 months before randomization that required hospitalization or outpatient diuretic treatment,
• Confirmed diagnosis of chronic heart failure with reduced ejection fraction (LVEF ≤ 40%, confirmed by echocardiography) within 12 months before randomization,
• Stable GDMT for HFrEF for at least 3 months prior to randomisation.

Exclusion Criteria:

• Systolic blood pressure < 100 mmHg or symptomatic hypotension,
• Current or planned use of long-acting nitrates, soluble guanylate cyclase stimulators, or phosphodiesterase type V inhibitors,
• Known allergy/hypersensitivity to soluble guanylate cyclase stimulators,
• Awaiting heart transplantation or dependence on continuous inotropic therapy
• Cardiac amyloidosis, sarcoidosis, myocarditis, stress cardiomyopathy, or tachycardic cardiomyopathy,
• Acute coronary syndrome, coronary artery bypass grafting, or percutaneous coronary intervention in the past three months before randomisation,
• Long-term mechanical circulatory support of the left ventricle,
• Active infection,
• Chronic kidney disease stage 4 or 5, and
• Advanced liver failure classified as Child-Pugh B or C.

Deidentified individual participant data (IPD) that underlie the results reported in future publications (text, tables, figures, and appendices) will be shared upon reasonable request. Shared IPD will include baseline characteristics, outcome measures, and relevant biomarker data, excluding data that could compromise participant privacy or institutional confidentiality.

IPD will be made available within 6 months after publication of the main results and will remain accessible for at least 5 years thereafter.

Researchers whose proposed use of the data is approved by the principal investigator will be granted access. Proposals should include a concise research plan and statistical analysis outline. Requests should be submitted to tine.bajec@kclj.si. Approved requesters will sign a data sharing agreement to ensure data confidentiality and appropriate use.