Discovery of a potent sGC stimulator with once-daily dosing potential for the treatment of hypertension.

Despite foundational quadruple guideline-directed medical therapy (GDMT), patients with heart failure with reduced ejection fraction (HFrEF) face substantial residual risk. Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, provides a crucial therapeutic option by directly targeting the impaired NO-sGC-cGMP signaling pathway to mitigate this risk. This review synthesizes current literature tracking vericiguat's trajectory from pivotal clinical trials (VICTORIA, VELOCITY, and VICTOR) to its emerging real-world implementation. We examine its efficacy, hemodynamic and renal tolerability, and safety profile across the HFrEF spectrum. Additionally, we provide a framework for clinical decision-making, addressing optimal patient selection, initiation timing, and the navigation of polypharmacy. Current evidence suggests that vericiguat may represent a valuable adjunctive therapy for selected high-risk patients with HFrEF, with a generally favorable hemodynamic and renal tolerability profile that appears not to substantially exacerbate hypotension or hyperkalemia when integrated with contemporary guideline-directed medical therapy. To maximize its real-world implementation, clinicians must overcome clinical inertia and embrace the purposeful deprescribing of non-essential symptomatic medications. Future research should prioritize advanced renal disease cohorts and biomarker-guided phenotyping, ultimately shifting vericiguat from a reactive post-decompensation therapy to an earlier, proactive intervention within a personalized treatment strategy.

Contemporary pharmacotherapy of chronic heart failure with reduced ejection fraction (HFrEF) consists of angiotensin receptor-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium glucose cotransporter 2inhibitors. In this year two more agents were added to the existing armamentarium: (1)digitoxin as inhibitor of sodium-potassium-ATPase and (2)vericiguat as stimulator of soluble guanylate cyclase. Vericiguat has already been shown to reduce cardiovascular death and heart failure hospitalization in patients with recent decompensation. This year it was tested in stable heart failure without prior recent decompensation; however, in this case there was no reduction for the combined endpoint of cardiovascular mortality and hospitalization. In the secondary endpoint analysis mortality was significantly reduced. In addition, ameta-analysis including combined data from patients with unstable and also stable heart failure confirmed the positive effects of vericiguat on cardiovascular death and heart failure hospitalization. In the DIGIT-HF study low-dose digitoxin (serum level8-18 ng/l) significantly reduced death and heart failure hospitalization. Both studies provide evidence that digitoxin and vericiguat added significant benefits to the established 4‑pillar pharmacotherapy and the treatment of HFrEF will be expanded by two more pillars.

Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality, imposing an increasing clinical and socioeconomic burden. Despite significant therapeutic advances, optimal control of risk factors and long-term outcomes remain challenging, particularly in patients with complex comorbidities. This narrative review provides a comprehensive and up-to-date synthesis of pharmacological options across major cardiovascular domains, with a specific focus on hypertension, heart failure, arrhythmias, and hypertrophic cardiomyopathy, conditions in which hemodynamic, neurohormonal, and electrophysiological pathways play central roles. We summarize mechanisms of action, clinical evidence, safety profiles, and guideline-based indications of established therapies, highlighting their relevance to vascular tone regulation, neurohormonal modulation, endothelial signaling, and myocardial function, the mechanistic axes that intersect with pathways implicated in pulmonary vascular disease (PVD). In addition, we discuss emerging therapeutic targets and innovative agents such as renin-angiotensin-aldosterone system silencers, endothelin pathway modulators, SGLT2 inhibitors, soluble guanylate cyclase stimulators, myosin inhibitors, and other mechanism-based approaches. Current challenges and unmet clinical needs are examined in the context of translational relevance for PVD and the broader goal of advancing individualized pharmacotherapy. Continued therapeutic innovation targeting shared vascular, metabolic, and neurohormonal pathways holds promise for improving outcomes across both systemic and pulmonary vascular diseases.

Vericiguat, a soluble guanylate cyclase stimulator, regulates heart failure-enhanced atrial and pulmonary vein arrhythmogenesis.

Vericiguat protects against doxorubicin-induced myocardial injury by modulating glycolysis and histone lactylation through RELB regulation.

Vascular calcification (VC), a pathological process driven by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), markedly increases cardiovascular mortality. Vericiguat, a soluble guanylate cyclase stimulator, has shown vascular protective properties, but its role in modulating VC remains poorly investigated. VC models were generated using the nephrectomy method or an adenine diet. Calcification in rat VSMCs and aortic rings was induced by high phosphate. VC was evaluated by Alizarin Red staining, calcium quantification, alkaline phosphatase activity, and imaging. Transcriptomic profiling and viral vector approaches were used to investigate the role of MMP-10 (matrix metalloproteinase 10) in vericiguat-regulated VC. Vericiguat treatment significantly reduced aortic calcification and osteogenic markers of VSMCs both in nephrectomy-induced rats and adenine-induced mice. It also inhibited calcium deposition and the phenotypic switch of VSMCs from a contractile to an osteoblastic state in both aortic ring and VSMC cultures. Transcriptomic profiling identified MMP-10 as a key mediator; MMP-10 was upregulated in VC models, and vericiguat reduced its expression. Overexpression of MMP-10 reversed the protective effects of vericiguat, and lentiviral-mediated MMP-10 knockdown confirmed its procalcific role. Mechanistically, vericiguat increased cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) signaling, including phosphorylated vasodilator-stimulated phosphoprotein and phosphorylated c-Jun (transcription factor Jun), ultimately downregulating MMP-10. Vericiguat inhibits VSMC osteogenic differentiation and attenuates VC by modulating the cGMP-PKG-MMP-10 axis. These findings support vericiguat as a potential therapeutic candidate for VC.

Randomized controlled trial of vericiguat in patients with coronary microvascular dysfunction causing stable chest pain (V-COM): study protocol for a randomized control trial\u2606

Vericiguat is the first oral soluble guanylate cyclase (sGC) stimulator developed to reduce the risk of cardiovascular death and heart failure–related hospitalizations in patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF). sGC dysfunction, resulting in impaired synthesis of cyclic guanosine monophosphate (cGMP), may play a keyrole in the pathophysiology of heart failure by affecting myocardial function, vascular tone, and peripheral tissue perfusion. Vericiguat exerts its therapeutic effect by enhancing intracellular cGMP levels, leading to improved cardiac function and vasodilation. Consequently, the drug represents a promising treatment option for patients with HFrEF, particularly those with recent decompensation, requiring intravenous diuretic therapy, or at high risk for rehospitalization due to disease exacerbation. Clinical efficacy of vericiguat was demonstrated in the VICTORIA trial, which enrolled 6,857 patients with HFrEF following recent decompensation. After a median follow-up of 10.8 months, treatment with vericiguat significantly reduced the risk of the composite endpoint of cardiovascular death or heart failure related hospitalization compared with placebo. Patients with more advanced disease also exhibited reductions in NT-proBNP levels, suggesting a potential biomarker of therapeutic response. Vericiguat is generally well tolerated. The most commonly reported adverse events are hypotension and syncope. The drug can be safely administered to patients with mild to moderate renal or hepatic impairment, although data in severe organ dysfunction are lacking. Dose adjustments are not required based on age or body weight. The introduction of vericiguat into the management of HFrEF represents a meaningful advancement in therapy. While the drug does not significantly extend overall survival, its use is associated with a substantial reduction in the risk of recurrent hospitalizations, which may have important clinical and prognostic implications in this patient population.

Vericiguat is a soluble guanylate cyclase stimulator that acts by restoring the nitric oxide-cyclic guanosine monophosphate pathway, which is markedly impaired in heart failure with reduced ejection fraction (HFrEF). The VICTORIA trial demonstrated that treatment with vericiguat leads to a significant reduction in mortality and morbidity in patients with HFrEF and a recent episode of clinical decompensation. However, the role of vericiguat in clinically stable patients had remained unexplored until the recent publication of the VICTOR trial. In a population receiving optimal medical therapy and characterized by a lower risk of events, vericiguat did not demonstrate a significant reduction in the primary composite endpoint of cardiovascular death and hospitalization for heart failure. When analysing the individual components of the primary endpoint, no benefit was observed with respect to hospitalizations, whereas significant reductions in both cardiovascular and all-cause mortality were reported. This finding, which is highly unusual in the context of recent clinical trials in patients with HFrEF, warrants further consideration when interpreting the results of the study.

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.

Pulmonary hypertension (PH) is a progressive, life-threatening condition characterized by elevated pulmonary arterial pressure, often culminating in right heart failure. Despite existing therapies, optimizing treatment efficacy and safety remains a clinical challenge. Riociguat, a soluble guanylate cyclase stimulator, has shown promise in managing PH, particularly in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). This meta-analysis aims to evaluate the optimal dosing of riociguat to maximize therapeutic benefits while minimizing adverse effects. This systematic review and meta-analysis followed PRISMA guidelines. A comprehensive search of PubMed, Cochrane Central, Embase, and Google Scholar was conducted to identify randomized controlled trials (RCTs) comparing riociguat with placebo in adult PH patients. Eligible studies included double-arm RCTs with riociguat dosages ranging from 0.5 to 2.5 mg. Primary outcomes included changes in 6-minute walk distance (6-MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and NT-proBNP levels. Secondary outcomes were adverse events and clinical worsening. Study quality was assessed using the Cochrane risk of bias tool. Statistical analysis used RevMan 5.4 with a random-effects model. Heterogeneity was evaluated using χ2 and I2 tests, and meta-regression assessed the impact of age and BMI. Ten RCTs involving 1109 PH patients were included. Riociguat significantly improved 6-MWD (MD: 27.23 m; 95% CI: 8.28-46.18; P = .005), reduced mPAP (MD: -2.61 mm Hg; 95% CI: -4.60 to -0.63; P = .01), lowered PVR (MD: -90.27 dynes·s·cm-5; 95% CI: -119.30 to -61.23; P < .00001), and decreased NT-proBNP levels (MD: -256.77 pg/mL; 95% CI: -491.99 to -21.55; P = .03). Meta-regression showed age and BMI significantly influenced treatment effects. Riociguat demonstrates dose-dependent efficacy in improving functional and hemodynamic parameters in PH, with the 2.5 mg thrice-daily dose showing consistent benefit. BMI impacted functional outcomes but not hemodynamic measures. These findings support tailored dosing strategies for optimized patient outcomes. Further research is needed to confirm dose-response effects and address residual heterogeneity.

Pulmonary hypertension is a life-threatening condition with limited therapeutic options. Riociguat, a soluble guanylate cyclase stimulator, is approved for pulmonary arterial and chronic thromboembolic pulmonary hypertension, but oral administration results in variable systemic exposure and adverse effects. This study aimed to evaluate the intratracheal pharmacokinetics and pulmonary retention of riociguat in mice, comparing a suspension and a dimethyl sulfoxide (DMSO)-based solution. Pharmacokinetic parameters, including maximum concentration (Cmax), time to maximum concentration (Tmax), half-life (t1/2), mean residence time (MRT), systemic exposure, and tissue distribution (lung, kidney, and liver), were determined. Lung histology was also assessed. The solution demonstrated higher dose-corrected plasma Cmax/D (0.278 vs. 0.128 ng/mL/μg) and shorter systemic retention (MRT0-∞: 3.57 vs. 4.43 h) compared with the suspension, while systemic exposure remained similar. In lung tissue, the suspension exhibited prolonged retention with longer t1/2 (13.54 vs. 5.17 h) and MRT0-∞ (13.37 vs. 7.82 h), indicating sustained pulmonary exposure. No histological changes were observed with the DMSO-based formulation. The suspension provided extended lung retention but contained large particles (10–100 μm) unsuitable for inhalation. Particle engineering to develop optimised suspension or dry powder formulations may enable efficient lung deposition and improve riociguat inhalation therapy.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, chronic, progressive, and life-limiting condition with a poor five-year survival in untreated patients with advanced disease. Multi-modality imaging techniques are used in making the diagnosis and determining treatment options in CTEPH. Pulmonary endarterectomy (PEA) surgery is the treatment of choice in selected patients, providing excellent long-term survival. Balloon pulmonary angioplasty (BPA) is an established intervention for selected patients who are not suitable for surgery. Riociguat, a soluble guanylate cyclase stimulator, is a vasodilator and indicated in patients with inoperable disease. In this state-of-the-art review, we provide an update in the diagnostic evaluation with a focus on imaging modalities, treatment strategies, and future directions in CTEPH.

Heart failure (HF) remains a major global health burden, with mortality continuing to rise despite therapeutic advances. Vericiguat, a soluble guanylate cyclase stimulator, has demonstrated potential benefit in patients with worsening HF with reduced ejection fraction (HFrEF), although results across randomized trials have been inconsistent. We conducted a systematic literature search across PubMed, Scopus, and ClinicalTrials.gov for relevant articles from inception through September 30th, 2025. Outcomes were reported as pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Statistical significance was defined as a 95% confidence interval not crossing 1.0 with a two-tailed p-value < 0.05. Five randomized controlled trials (RCTs) with 12,877 patients (6857 in the vericiguat group and 6020 in the placebo group) were included. Vericiguat demonstrated a borderline but non-significant reduction in composite outcome of cardiovascular death (CVD) or hospitalization for HF (OR 0.92, 95% CI 0.85-1.00; p = 0.05), hospitalization for HF (OR 0.93, 95% CI 0.85-1.02; p = 0.14), and all-cause mortality (ACM) (OR 0.91, 95% CI 0.81-1.01; p = 0.07). The findings of this study suggest that Vericiguat, when added to guideline-directed medical therapy in patients with heart failure, was associated with a borderline, non-significant reduction in the risk of the composite outcome of cardiovascular death or heart failure hospitalization, as well as all-cause mortality. Further large-scale randomized trials are warranted to better define its clinical benefit.

Despite advances in guideline-directed medical therapy (GDMT), heart failure with reduced ejection fraction (HFrEF) remains a progressive condition with high morbidity and mortality. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, represents a novel therapeutic class that augments the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) pathway, which is impaired in HFrEF. The VICTORIA trial demonstrated that vericiguat significantly reduced the composite endpoint of cardiovascular death or heart failure hospitalization (HFH) in high-risk patients following a worsening event. Recent data from the VICTOR trial and subsequent pooled analyses suggest broader applicability, indicating that vericiguat may signal a potential mortality benefit in selected stable, ambulatory HFrEF patients with elevated natriuretic peptides but without recent hospitalization. The safety profile is favorable, with hypotension being the most common adverse event. Overall, vericiguat offers a valuable therapeutic option for a wide spectrum of HFrEF patients. Moreover, the ability of vericiguat to improve outcomes in both post-worsening and selected high-risk stable populations suggests this sGC stimulator may serve as a critical fifth component of GDMT, offering a new avenue for a personalized approach to HFrEF treatment. This review synthesizes key clinical evidence to elucidate the role of vericiguat in modern HFrEF management.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive vascular disorder characterized by persistent thromboembolic obstruction and fibrotic remodeling of the pulmonary arteries. Although autophagy has been implicated in various forms of pulmonary hypertension, its specific role in CTEPH pathogenesis remains unclear. In this study, histological, immunohistochemical, and molecular analyses of pulmonary artery lesions from CTEPH patients revealed increased collagen deposition and elevated expression of autophagy markers beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3) compared to non-CTEPH controls. Primary pulmonary artery endothelial cells (PAECs) derived from CTEPH patients exhibited dysregulated autophagy-related protein expression. Mechanistically, TGF-β stimulation induced autophagy via the Smad3 signaling pathway. Notably, riociguat, a soluble guanylate cyclase stimulator approved for CTEPH, modulated autophagy-related proteins in vitro. In hypoxia- and TGF-β-induced pulmonary hypertension mouse models, riociguat attenuated LC3 but not beclin-1 expression and significantly reduced right ventricular systolic pressure. These findings suggest that LC3 may be a key autophagy marker in CTEPH. These findings identify the TGF-β/Smad3-LC3 axis as a critical mechanism driving CTEPH and suggest that pharmacological modulation of autophagy, particularly via riociguat, offers a promising therapeutic opportunity, especially for patients ineligible for surgical intervention. KEY MESSAGES: Beclin-1 and LC3, key autophagy markers, are upregulated in thrombofibrotic pulmonary arteries from patients with CTEPH. TGF-β activates autophagy in pulmonary artery endothelial cells through the Smad3 signaling pathway. Riociguat treatment downregulates LC3 expression, improves pulmonary hemodynamics, and reduces vascular remodeling in experimental PH models. LC3 as a potential biomarker and therapeutic target in the progression of CTEPH driven by autophagy.

Contrast-induced nephropathy (CIN) is an important cause of acute kidney injury following exposure to iodinated contrast media, and effective preventive strategies remain limited. This study investigated the renoprotective effects of riociguat, a soluble guanylate cyclase stimulator, in an experimental rat model of CIN and explored machine-learning-based prediction of renal injury using histopathological, biochemical, and inflammatory markers. Thirty-six female Wistar albino rats were randomized into control, riociguat, CIN model, and CIN + riociguat groups. CIN was induced by iohexol after dehydration, and riociguat was administered orally for 5 days. Renal injury was assessed by histopathological scoring, TUNEL assay, and biochemical parameters including serum creatinine, urea, tumor necrosis factor-alpha, nitric oxide, neutrophil gelatinase-associated lipocalin, and advanced oxidation protein products. Riociguat significantly decreased serum creatinine, urea, apoptotic index, and histopathological injury scores, reduced inflammatory and oxidative stress markers, and increased nitric oxide levels compared with untreated CIN animals (p < 0.05). Machine learning models (Random Forest, CatBoost, AdaBoost, and XGBoost) were applied for exploratory prediction and feature importance analysis. The apoptotic index and nitric oxide were identified as dominant predictors, indicating mechanistic relevance but limited clinical screening utility because these predictors require histological assessment. Overall, riociguat demonstrated significant renoprotective effects through anti-apoptotic, anti-inflammatory, and antioxidative mechanisms, and machine learning provided hypothesis-generating insight rather than a clinically deployable predictive model.

Vericiguat, a soluble guanylate cyclase stimulator, has been shown to be effective in improving the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) and worsening heart failure. We sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with HFrEF treated with vericiguat. Improved FMD values were found after 3 months of therapy with vericiguat (19 ± 11 vs. 15 ± 10% FMD, P = 0.04). FMD variation at follow-up was inversely related to baseline FMD values ( r = -0.52, P = 0.001). Three months of therapy with vericiguat in patients with HFrEF and worsening heart failure were associated with improved endothelial function assessed by FMD.

Vericiguat, a soluble guanylate cyclase stimulator, is recommended for patients with chronic heart failure (HF) who recently worsened despite guideline-directed medical therapy. However, there is limited data on its real-world utilization and outcomes. The ROVER-Japan study examined prescribing patterns and prognosis among Japanese patients who initiated vericiguat in routine practice. This retrospective cohort study analyzed secondary data from a Japanese hospital administrative database. Among adult patients diagnosed with HF, 4936 patients who initiated a starting dose of vericiguat (2.5mg/day) on top of any fundamental HF therapy between September 15, 2021, and July 31, 2024, were included. Patients were followed for up to one year or until death, loss to follow-up, or the end of the study period. The mean age of the included patients was 75.4 (standard deviation 12.4) years. At vericiguat initiation, 60.4% of the patients had a recent worsening HF event, defined as HF hospitalization (HFH) in the previous six months or outpatient intravenous diuretics in the previous three months. Quadruple guideline-directed therapy was administered to 29.6% of patients at baseline. One year after treatment initiation, 95.7% of patients had a medication possession ratio≥80%, and 66.6% continued vericiguat treatment. Natriuretic peptide levels and diuretic use decreased, while eGFR remained stable after vericiguat initiation. The one-year cumulative incidence of composite of cardiovascular death or HFH was 29.8%. This study provides real-world insights into the contemporary use and outcomes of vericiguat in a large, diverse HF population.