Vericiguat is a soluble guanylate cyclase stimulator previously shown to improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying mechanisms remain incompletely understood. To evaluate the feasibility of assessing the effects of vericiguat on endothelial function, we conducted a pilot, randomized, double-blind, placebo-controlled trial of vericiguat in patients with HFrEF. Feasibility and efficacy outcomes were assessed at baseline and at 12 weeks on treatment. The primary efficacy outcome was brachial artery flow-mediated vasodilation. Secondary efficacy outcomes included N-terminal pro-brain natriuretic peptide, inflammatory markers, functional capacity, and health-related quality of life. An analysis of covariance model was used for continuous and Mantel–Haenszel tests for discretized outcomes. We enrolled 26 participants (median age 67 years, 84% male), with 25 completing 12-week follow-up, 13 in the active and 12 in the control arm. Feasibility objectives were successfully met, including enrollment, retention, drug titration, and completeness of data collection for all endpoints. In exploratory analyses, treatment with vericiguat resulted in flow-mediated dilation mean difference of 0.7%, (95% confidence interval: −1.1% to 2.5%, p = 0.40) and a nominally significant reduction of log NTproBNP of −0.42 (95% confidence interval: −0.81 to −0.04, p = 0.03). No significant differences in inflammatory biomarkers, functional capacity, or health-related quality of life were observed. We demonstrated the feasibility of assessing endothelial function in patients with HFrEF treated with vericiguat. While the pilot study size did not provide sufficient precision to confirm a treatment effect, our findings support future larger and longer studies to evaluate the therapeutic potential of soluble guanylate cyclase stimulation on endothelial function in HFrEF.
The burden of heart failure (HF) continues to increase, with approximately 6.7 million Americans over 20 years of age currently diagnosed, and its prevalence is expected to rise to 8.7 million by 2030. HF with reduced ejection fraction (HFrEF) has been associated with significant morbidity, mortality, and healthcare burden. Despite advances in pharmacologic and device-based therapies, many patients continue to experience disabling symptoms and diminished quality of life. Novel therapeutic options have been proposed to address the needs especially in patients who remain symptomatic despite optimal guideline-directed medical therapy (GDMT). In this context, the cyclic guanosine monophosphate (cGMP) pathway has emerged as a therapeutic target, particularly due to its mechanistic effects on endothelial function, nitric oxide (NO) signaling, and inflammation.
Vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, enhances cGMP production independently of NO. In the VICTORIA (VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat reduced the risk of cardiovascular death or HF hospitalization in patients with HFrEF, yet the precise mechanisms underlying this benefit remain uncertain. Further analyses from the VICTORIA trial suggested no significant changes in left ventricular ejection fraction (LVEF), while in earlier phase studies, higher-dose vericiguat was associated with a modest improvement in LVEF without corresponding changes in left ventricular volumes. These data raised the hypothesis that vericiguat’s therapeutic effects may be mediated through an improvement in endothelial function rather than direct myocardial effects, yet this important question has not been evaluated in the clinical setting.
Endothelial dysfunction is a hallmark of HFrEF and is linked to impaired vasodilation, chronic inflammation, reduced exercise tolerance, and worse health-related quality of life (hrQOL). ,,, Flow-mediated dilation (FMD), a noninvasive measure of endothelial function, is often impaired in HFrEF, even in patients receiving optimized GDMT. ,,, Emerging data suggest that endothelial dysfunction may be a modifiable contributor to poor outcomes in HFrEF, and therapies targeting vascular health may offer substantial clinical benefits. ,
In this pilot randomized, placebo-controlled study, we evaluated the feasibility of assessing the effect of vericiguat on endothelial function, inflammation, physical capacity, and patient-reported health status over 12 weeks of treatment in patients with HFrEF. Exploratory analysis included the treatment effect of vericiguat in endothelial function, inflammatory biomarker levels, and functional and hrQOL measures. This study is one of the first efforts to directly examine the vascular and inflammatory effects of vericiguat in a HFrEF population.
Methods
Trial design and ethical approval
This was a single-center, randomized, double-blind, placebo-controlled trial conducted at the University of Utah and the Salt Lake City Veterans Affairs Medical Center. The study protocol was approved by the Institutional Review Boards (IRB) of both participating institutions (IRB: 00152530). All aspects of the study conformed to the standards set by the Declaration of Helsinki, except for registration in a database. All experimental procedures were explained to participants in writing and verbally, and written informed consent was obtained from all participants before study participation. The trial was investigator-initiated and supported by Merck Investigator Study Program and the University of Utah. The investigators were responsible for the study design, data collection, data analysis, and interpretation of results. Statistical analyses were performed by the study statisticians and independently reviewed by the study team.
Study population
Eligible participants were adults (≥18 years) with HFrEF and New York Heart Association class II or III symptoms. Further inclusion criteria included a LVEF ≤ 45% within the past 12 months, systolic blood pressure ≥90 mm Hg, and optimized use of GDMT. The full list of inclusion and exclusion criteria is provided in Supplemental Methods .
Randomization and treatment
Following the screening visit, eligible participants were randomly assigned in a 1:1 ratio to receive either vericiguat or matching placebo for a total of 12 weeks. Randomization was stratified by participating site, used randomly permuted blocks, and was performed by a computer-generated randomization software managed by the study investigational pharmacy. Study drug was administered once daily, starting at 2.5 mg, increased to 5 mg at week 2, and to the target dose of 10 mg at week 4 as tolerated, guided by blood pressure (BP) and clinical symptoms. To enhance the likelihood of achieving and maintaining the target dose of 10 mg, investigators were encouraged to address dosing at each visit according to the patient’s BP and symptomatic status. Patients were evaluated for study-related adverse events at weeks 2, 4, 8, and 12. Throughout the study, participants remained on GDMT for HFrEF. Both participants and study personnel were blinded to treatment allocation throughout the trial. Study drug dispensing and compliance monitoring were coordinated through the investigational pharmacy.
Trial conduct
All data collection took place with patients in the supine position in a thermoneutral environment. All patients reported to the laboratory at least 4 hours postprandial, having taken their medication with food or water according to their usual routine, and abstained from caffeine, alcohol, and exercise for 24 hours prior. Data collection included anthropometrics, venous blood samples, BP, endothelial function (brachial artery FMD), functional capacity via the six-minute walk test (6MWT), and hrQOL assessment via standardized questionnaires (Kansas City Cardiomyopathy Questionnaire-12 [KCCQ-12], visual analog scale [VAS]). To minimize physiologic interference between assessments, FMD was performed first, followed by blood sample collection, and subsequently by the 6MWT. Venous blood samples were processed using standard clinical procedures at the Salt Lake City Veterans Affairs Medical Center and at the University of Utah Hospital. Follow-up testing occurred while participants were receiving study drug and at the same time of day for baseline and 12-week visits; assessments were not timed to a fixed interval after the last received dose.
Brachial artery FMD measurements and analysis
FMD testing for the assessment of conduit artery endothelial function was performed in accordance with established guidelines. A detailed description of the FMD assessment protocol is provided in Supplemental Methods .
Blood biomarker assays
Blood samples were centrifuged to collect plasma and serum, and either directly analyzed or stored at −80°C until analysis. A detailed description of the biomarkers assessment protocol is provided in Supplemental Methods .
Six-minute walk test
The 6MWT was conducted following a standardized protocol. Patients were instructed to cover the maximum distance possible in 6 min, at a self-selected walking speed, and were unaccompanied and without verbal encouragement, to avoid any social influence on the walking speed. The 6MWT distance is used to estimate functional capacity and is highly reproducible in patients with HFrEF.
hrQOL instruments
Both disease-specific and generic patient-reported outcome metrics were used. HF-specific health status was assessed with the KCCQ-12. The KCCQ-12 has been shown be a valid, reliable, and sensitive measure in a variety of causes of HF. Generic health status was assessed with a VAS.
Outcomes
The primary outcome was endothelium-dependent vascular function at 12 weeks, measured by brachial artery FMD. Secondary outcomes included circulating biomarkers, functional capacity, and hrQOL at 12 weeks. Circulating biomarkers of inflammation and cardiac stress included high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-18, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Functional capacity was assessed via the 6MWT. HrQOL was measured using the KCCQ-12 overall summary score and a VAS.
Statistical analysis
Patient baseline characteristics were summarized by assignment group (vericiguat and placebo). Standard summary descriptions were used, including frequencies, percentages, and medians. Measures of variation were presented as the median (interquartile range). All analyses were conducted on an intention-to-treat basis. For each continuous variable (FMD, 6MWT, KCCQ, VAS, log hsCRP, log NT-proBNP, and log IL-18), an analysis of covariance model was used, modelling the 12-week measurement as the dependent variable and the vericiguat treatment as the treatment variable, while adjusting for the baseline measurement. The biomarkers hsCRP, NT-proBNP, and IL-18 were log-transformed to address skewness. The biomarkers TNF-α and IL-6 were discretized into binary variables due to high rates of values below the detection limit of the assay. Cutoff values were defined according to clinically meaningful thresholds established in prior studies. ,, For these discretized biomarkers TNF-α and IL-6, we used Mantel–Haenszel tests to assess the association between treatment and biomarker detectability at 12 weeks, stratified by baseline detectability status. As the purpose of this trial was to evaluate feasibility, the sample size was not sufficient to determine treatment effect. Accordingly, we provide point estimates and 95% confidence intervals (CI) for all treatment comparisons on outcomes, and report 2-sided p values, but interpret analyses of treatment effects as exploratory. All computations were conducted using R version 4.4.2 (R Core Team 2024).
Results
Study participants
A total of 26 participants were enrolled at 2 sites from May 25, 2023, through July 18, 2024, and follow-up was completed on October 10, 2024. Twenty-five (96%) participants completed the 12-week follow-up, with 1 participant in the placebo group lost to follow-up after 25 days due to relocation.
Baseline characteristics of the patients are shown in Table 1 . The median age of enrolled patients was 67 (57, 73) years, 84% were male, and 96% were White. At randomization, 76% of participants were classified as New York Heart Association Class II, and had a median LVEF of 33 (27, 39) %. Most patients were receiving comprehensive GDMT, including beta-blockers (100%), angiotensin converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor/neprilysin inhibitor (88%), mineralocorticoid receptor antagonists (92%), and sodium-glucose cotransporter-2 inhibitors (60%). Diuretics were prescribed to 88% of participants, the majority of whom (59%) received a furosemide equivalent daily dose of 40 mg ( Table 1 ).
Table 1
Characteristics of the patients at baseline
| Characteristic |
Overall
N = 25 |
Placebo
N = 12 |
Vericiguat
N = 13 |
|---|---|---|---|
| Age (years) | 67 (57, 73) | 67 (59, 71) | 68 (52, 79) |
| Sex | |||
| Female | 4 (16%) | 1 (8.3%) | 3 (23%) |
| Male | 21 (84%) | 11 (92%) | 10 (77%) |
| Ethnicity | |||
| Not Hispanic or Latino | 24 (96%) | 12 (100%) | 12 (92%) |
| Hispanic or Latino | 1 (4.0%) | 0 (0%) | 1 (7.7%) |
| Race | |||
| White | 24 (96%) | 12 (100%) | 12 (92%) |
| Native Hawaiian or Other Pacific Islander | 1 (4.0%) | 0 (0%) | 1 (7.7%) |
| Body mass index (kg/m 2) | 30.8 (28.8, 34.5) | 30.9 (29.6, 34.0) | 29.3 (26.7, 34.5) |
| Systolic blood pressure (mm Hg) | 109 (97, 124) | 99 (91, 122) | 112 (106, 126) |
| Diastolic blood pressure (mm Hg) | 71 (63, 76) | 70 (62, 75) | 75 (67, 79) |
| Heart rate (bpm) | 65 (59, 70) | 66 (61, 74) | 64 (52, 70) |
| Comorbidities | |||
| Ischemic cardiomyopathy | 9 (36%) | 5 (42%) | 4 (31%) |
| NYHA class | |||
| II | 19 (76%) | 8 (67%) | 11 (85%) |
| III | 6 (24%) | 4 (33%) | 2 (15%) |
| Hypertension | 18 (72%) | 7 (58%) | 11 (85%) |
| Atrial fibrillation | 12 (48%) | 4 (33%) | 8 (62%) |
| Type 2 diabetes mellitus | 14 (56%) | 8 (67%) | 6 (46%) |
| Hyperlipidemia | 14 (56%) | 8 (67%) | 6 (46%) |
| Coronary artery disease | 12 (48%) | 7 (58%) | 5 (38%) |
| Peripheral vascular disease | 2 (8.0%) | 1 (8.3%) | 1 (7.7%) |
| Echocardiography parameters | |||
| LVEF (%) | 33 (27, 39) | 27 (24, 39) | 36 (33, 39) |
| LVIDd (cm) | 6.10 (5.50, 6.40) | 6.10 (5.50, 6.30) | 6.10 (5.50, 6.60) |
| Laboratories | |||
| Hemoglobin (g/dL) | 15.20 (13.80, 16.20) | 15.25 (14.00, 16.20) | 14.50 (13.50, 16.80) |
| Hematocrit (%) | 45.3 (41.6, 48.0) | 46.7 (42.2, 48.8) | 44.0 (41.6, 47.2) |
| White blood cells (10 9/L) | 7.10 (6.23, 8.17) | 6.48 (6.20, 7.90) | 7.75 (6.49, 8.22) |
| Sodium (mEq/L) | 139.00 (138.00, 140.00) | 139.00 (138.00, 140.00) | 139.00 (138.00, 141.00) |
| Potassium (mEq/L) | 4.40 (4.30, 4.50) | 4.40 (4.30, 4.50) | 4.40 (4.30, 4.50) |
| Creatinine (mg/dL) | 1.14 (1.04, 1.44) | 1.13 (0.99, 1.34) | 1.14 (1.06, 1.64) |
| Blood urea nitrogen (mg/dL) | 21.0 (18.0, 28.0) | 20.0 (16.5, 27.5) | 22.0 (20.0, 29.0) |
| Glucose (mg/dL) | 100 (88, 135) | 118 (88, 133) | 98 (88, 135) |
| Concomitant medications | |||
| Beta blockers | 25 (100%) | 12 (100%) | 13 (100%) |
| ACEI/ARB/ARNI | 22 (88%) | 10 (83%) | 12 (92%) |
| MRA | 23 (92%) | 12 (100%) | 11 (85%) |
| SGLT2i | 15 (60%) | 8 (67%) | 7 (54%) |
| Diuretics | 22 (88%) | 11 (92%) | 11 (85%) |
| Furosemide daily dose (mg) | |||
| 20 | 4 (18%) | 1 (9.1%) | 3 (27%) |
| 40 | 13 (59%) | 7 (64%) | 6 (55%) |
| 80 | 5 (23%) | 3 (27%) | 2 (18%) |
ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; LVEF = left ventricular ejection fraction; LVIDd = left ventricular internal diameter at end-diastole; MRA = mineralocorticoid receptor agonist; NYHA = New York Heart Association; SGLT2i = sodium-glucose cotransporter-2 inhibitor.
Study feasibility and drug titration
Feasibility goals were achieved, including timely enrollment, 100% successful randomization, and high data completeness for all outcomes. All randomized participants received at least one dose of study drug, and by week 4, the target dose of 10 mg once daily was achieved in 84% of participants overall, including 92% in the vericiguat group and 75% in the placebo group. At week 12, 91% of participants remained on the 10 mg dose (100% placebo, 83% vericiguat) ( Table 2 ). Adherence to study procedures was high, with complete primary outcome data collected in 96% ( n = 25) of randomized participants. Complete biomarker assessments were available for >98% of study visits. Functional status and hrQOL were evaluated for all randomized participants who completed the study ( n = 25, 96%).
Table 2
Vericiguat and placebo dosing achieved at weeks 4 and 12 follow-up visits by treatment group
Primary outcome
FMD was assessed in 26 patients at baseline and 25 at week 12 due to loss to follow-up of 1 participant in the placebo group. Mean FMD increased from 3.6% at baseline to 4.2% at 12 weeks in the vericiguat group but decreased from 3.7% at baseline to 3.6% at 12 weeks in the placebo group ( Table 3 , Supplementary Figure 1 ). At week 12, the adjusted mean FMD was 4.2% (95% CI: 3.00 to 5.47) in the vericiguat group versus 3.5% (95% CI: 2.24 to 4.81) in the placebo group (estimated treatment effect [ETE]:0.71, 95% CI: −1.1 to 2.5; p = 0.40) ( Figure 1 ). Baseline and 12-week measurements of baseline brachial artery diameter, peak brachial artery diameter, shear rate area under the curve, FMD/shear rate area under the curve, and BP are shown in Supplementary Table .
Table 3
Descriptive summary of study outcomes
| Placebo | Vericiguat | |||
|---|---|---|---|---|
| Outcome |
Baseline
N = 12 * |
Week 12
N = 12 * |
Baseline
N = 13 * |
Week 12
N = 13 * |
| FMD (%) | 3.66 (1.33) | 3.55 (2.72) | 3.61 (2.36) | 4.22 (2.33) |
| NT-proBNP (pg/ml) | 623 (342) | 659 (482) | 1,306 (1,175) | 1,231 (1,290) |
| hsCRP (mg/L) | 2.93 (2.57) | 4.22 (4.28) | 2.90 (1.87) | 2.33 (1.77) |
| IL-18 (pg/ml) | 339 (193) | 334 (205) | 477 (275) | 461 (312) |
| IL-6 (pg/ml) | ||||
| <2.0 | 11 (92%) | 9 (75%) | 9 (69%) | 8 (62%) |
| ≥2.0 | 1 (8.3%) | 3 (25%) | 4 (31%) | 4 (31%) |
| TNF-α (pg/ml) | ||||
| <1.7 | 8 (67%) | 8 (67%) | 6 (46%) | 8 (62%) |
| ≥1.7 | 4 (33%) | 4 (33%) | 7 (54%) | 4 (31%) |
| 6MWT (m) | 398 (103) | 406 (97) | 390 (155) | 388 (148) |
| KCCQ-12 OSS (0–100) | 59 (20) | 66 (23) | 63 (22) | 68 (24) |
| VAS (0–100) | 66 (21) | 72 (13) | 55 (23) | 70 (20) |
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