Search Results (33)

Background and aims: Vericiguat lowers cardiovascular death or heart-failure hospitalization in recently worsened heart failure with reduced ejection fraction (HFrEF), but its effects on cardiac remodeling are less well characterized. Our aim was to evaluate whether the addition of vericiguat to guideline-directed medical therapy (GDMT) promotes reverse myocardial remodeling in patients with HFrEF and recent worsening. Methods: We conducted a prospective, non-randomized, single-center study enrolling 34 consecutive patients with HFrEF who had experienced recent worsening and were on stable GDMT for at least 3 months prior to decompensation. Clinical, biochemical, and echocardiographic assessments were performed at baseline and at 6 months. Results: A total of 24 patients completed the 6-month follow-up (mean age 63 ± 9 years; 92% male), 96% of whom were in New York Heart Association (NYHA) class III or IV. After 6 months of vericiguat therapy, right ventricular systolic function improved significantly, with an increase in tricuspid annular plane systolic excursion (TAPSE) from 18.5 ± 4.3 mm to 21.4 ± 4.8 mm (p = 0.003). Left ventricular systolic function improved, with a numerical increase in left ventricular ejection fraction (LVEF) (30.1 ± 5.9% to 32.2 ± 10.5%; p = 0.122) and a significant increase in left ventricular outflow tract velocity-time integral (LVOT VTI) (14.8 ± 3.7 cm to 16.1 ± 3.8 cm; p = 0.011). Functional improvements were accompanied by structural remodeling, including reductions in right ventricular internal diameter in diastole (RVIDd) (40.5 ± 5.8 mm to 37.9 ± 6.9 mm; p = 0.002) and left ventricular end-systolic volume (LVESV) (144.0 ± 40.3 mL to 132.4 ± 61.0 mL; p = 0.031). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels also decreased significantly (median 1829.0 ng/mL to 1241.0 ng/mL; p = 0.03). Conclusions: In patients with HFrEF and recent worsening, the addition of vericiguat to GDMT may be associated with reverse myocardial remodeling. Full article

Intravascular hemolysis, a hallmark of sickle cell disease (SCD), leads to elevated plasma heme levels. Although heme is essential for physiological processes, its excess can be deleterious. Heme oxygenase (HO) degrades heme into carbon monoxide (CO), which activates the soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling cascade and can modulate smooth muscle tone. However, the direct effects of heme on bladder function remain unknown. This study investigated whether heme regulates detrusor smooth muscle contractility through the HO–CO–sGC–cGMP pathway. Detrusor strips from C57BL/6 mice were mounted on a myograph for functional analysis. Heme induced a significant, concentration-dependent relaxation of detrusor smooth muscle compared with vehicle-treated tissues. To elucidate the underlying mechanism, tissues were pre-incubated with the sGC inhibitor ODQ (10 µM) or the HO inhibitor 1J (100 µM) before heme exposure. Both inhibitors markedly attenuated heme-induced relaxation, reducing the maximal relaxation response. Moreover, pre-incubation with heme (100 µM) significantly decreased the maximal contractile responses (Emax) to carbachol, KCl, and electrical field stimulation (EFS), effects that were abolished by ODQ or 1J. In parallel, biochemical assays showed that heme markedly increased cGMP levels in detrusor tissue, an effect prevented by both inhibitors, confirming the role of the HO–CO–sGC–cGMP signaling cascade in this response. These findings demonstrate that heme modulates bladder contractility by activating the HO–CO–sGC–cGMP pathway, promoting detrusor relaxation. This mechanism suggests that excessive circulating heme, as occurs in hemolytic disorders such as SCD, may contribute to detrusor hypocontractility and voiding dysfunctions, identifying this pathway as a potential therapeutic target. Full article

Pressure-overload-induced heart failure is characterized by pathological ventricular remodeling, including hypertrophy and fibrosis, which compromise cardiac function and worsen outcomes. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has shown therapeutic promise in heart failure with reduced ejection fraction (HFrEF). This study evaluated its antihypertrophic, antifibrotic, and metabolic effects in a murine pressure-overload model. Male C57BL/6 mice (~25 g) underwent transverse aortic constriction (TAC) and received oral Vericiguat (10 mg/kg/day) for 14 days. Cardiac hypertrophy was assessed by gross morphology and heart weight; fibrosis was quantified using Masson’s trichrome and Picrosirius red staining. Collagen deposition and wall stress indices were measured by image analysis. Proteomic profiling of fibroblast- and myocyte-enriched tissues identified differentially expressed proteins (DEPs) across metabolic, structural, mitochondrial, and signaling pathways. Vericiguat significantly reduced heart weight and attenuated TAC-induced hypertrophy. Histological staining revealed marked reductions in myocardial fibrosis and collagen accumulation in the Vericiguat-treated TAC group compared to untreated TAC controls. Quantitative analysis demonstrated improved wall stress indices. Proteomic data showed consistent modulation of DEPs, with restoration of mitochondrial and energy-regulating proteins suppressed by TAC, indicating enhanced bioenergetic support. Collectively, Vericiguat mitigates pressure-overload-induced remodeling through coordinated antihypertrophic, antifibrotic, and metabolic reprogramming mechanisms. These findings support its potential as a therapeutic strategy for heart failure and warrant further clinical investigation. Full article

The nitric oxide (NO) pathway is a fundamental regulator of vascular tone, myocardial function, and inflammation. In heart failure (HF), especially in advanced stages, dysregulation of NO–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling contributes to endothelial dysfunction, increased vascular resistance, myocardial fibrosis, and impaired cardiac performance. Chronic inflammation further reduces NO bioavailability, exacerbating HF progression This review synthesizes current knowledge on the role of the NO pathway in HF pathophysiology, with a focus on stable and advanced HF. Special attention is given to patient subgroups with comorbidities such as chronic kidney disease, where modulation of NO signaling may be particularly beneficial. We also evaluate therapeutic strategies targeting NO bioavailability and sGC stimulation. Evidence shows that impaired NO signaling promotes systemic and pulmonary vasoconstriction, elevates ventricular afterload, and worsens cardiac remodeling. Pharmacological agents that restore NO levels or activate downstream effectors such as sGC improve vasodilation, reduce fibrosis, and enhance myocardial relaxation. These effects are especially relevant in advanced HF patients and those with renal impairment, who often exhibit limited responses to conventional therapies. The NO pathway represents a promising therapeutic target in both stable and advanced HF. Modulating this pathway could improve outcomes, particularly in complex populations with multiple comorbidities, highlighting the need for further clinical research and tailored treatments. Full article

Background: Cisplatin (CP), a platinum-based chemotherapeutic agent, is widely used to treat cancer but causes nephrotoxicity. Riociguat, a soluble guanylate cyclase (sGC) stimulator that enhances the nitric oxide–sGC–cGMP signaling pathway, was investigated for its potential protective effects against cisplatin-induced nephrotoxicity. Materials and Methods: Rats were randomly divided into four equal groups (six rats each) and treated for nine consecutive days. The first and second groups were given oral carboxymethylcellulose 0.5% (vehicle) for 9 days, and on day 6 were injected intraperitoneally with saline or CP, respectively. The third and fourth groups were treated orally with two doses of riociguat (3 and 10 mg/kg/day) for 9 days, and received intraperitoneal injections of CP on day 6. Blood, urine, and kidney tissues were analyzed 24 h after the last treatment. Results: CP significantly elevated the markers of kidney function, including uric acid, serum creatinine, and urea. CP also caused histological kidney damage. Antioxidant markers, including catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), and total antioxidant capacity (TAC) were significantly reduced, while inflammatory cytokines (IL-1β, IL-6, and TNF-α) and lipid peroxidation (MDA) were markedly increased. Riociguat improved kidney structure and significantly reduced kidney function markers, MDA, and inflammatory cytokines while restoring GR, TAC, SOD, and CAT activities. Conclusions: These results indicate that riociguat exerts protection of the kidneys from CP-caused kidney damage by antioxidation and anti-inflammation. Riociguat may have potential as an adjunct therapy to mitigate CP-associated nephrotoxicity. Full article

The recent advancements in the medical management of patients with chronic heart failure with reduced ejection fraction (HFrEF) is the soluble guanylate cyclase (sGC) stimulator, vericiguat. Clinical trials have demonstrated that vericiguat effectively lowers plasma levels of NT-proBNP and reduces the risk of cardiovascular death or hospitalization in HFrEF patients, making it a class IIb recommendation for patients with worsening heart failure despite receiving guideline-directed medical therapy. However, the precise pathophysiological mechanisms underlying these clinical benefits remain unexplored. This review aims to present the signalling pathways associated with maladaptive remodeling and heart failure progression that can be modulated by sGC stimulators, focusing on the antihypertrophic, antifibrotic, and anti-inflammatory effects of NO–sGC–cGMP signalling observed in preclinical studies. A better understanding of the mechanisms of action of sGC stimulators could optimize heart failure treatment strategies and enable tailoring of therapies to individual patient profiles. Full article

Background: Vericiguat, a soluble guanylate cyclase stimulator, reduces cardiovascular events in patients with heart failure with reduced ejection fraction following clinical deterioration against guideline-directed medical therapy. However, the optimal timing for initiating vericiguat remains unclear. Methods: We retrospectively analyzed heart failure patients with reduced/mild-reduced ejection fraction who received vericiguat between 2021 and 2025 upon optimal guideline-directed medical therapy. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Patients were stratified by the number of prior heart failure hospitalizations (<2 vs. ≥2), and outcomes were assessed using multivariable Cox regression and biomarker trajectories over 6 months. Results: A total of 43 patients (with a median age of 73 years, 35 were men) were included. Of these, 26 (60%) patients had ≥2 prior hospitalizations. A number of hospitalizations ≥ 2 independently predicted the primary outcome (hazard ratio: 8.43; 95% confidence interval: 1.79–39.7; p = 0.007). Only patients with <2 prior hospitalizations showed significant improvements in plasma B-type natriuretic peptide levels (p = 0.049) and left ventricular ejection fraction (p = 0.016). In contrast, no meaningful biomarker changes were observed in patients with ≥2 hospitalizations. Conclusions: A history of two or more heart failure hospitalizations is a strong predictor of poor outcomes during vericiguat therapy. These findings suggest that initiating vericiguat earlier—before recurrent hospitalizations—may yield greater clinical benefit. Full article

The role of nitric oxide (NO), soluble guanylate cyclase (sGC), and the cyclic guanosine monophosphate (cGMP) pathway in cardiovascular and renal health and disease is a complex issue. The impact of these biochemical pathways on the vascular tree is well established: the activation of sGC by NO promotes vasodilation and modulates vascular tone. Indeed, additional characteristics exist that lead physicians to believe there is a pleiotropic influence of this pathway on the functional activities and structural characteristics of human tissues and cells. Recently, sGC stimulators have demonstrated clinical efficacy in patients with worsening heart failure with reduced ejection fraction, improving cardiovascular death risk, re-hospitalization for HF, and all-cause mortality. These new outcome data have increased interest in understanding the potential pathophysiological mechanisms. The NO-sGC-cGMP axis may influence endothelial function, kidney performance, and cardiac muscle cell activity. The synergy of these actions could explain the positive effects of vericiguat on worsening HF. The aim of this narrative review was to provide a comprehensive insight into the pathophysiological mechanisms of action of NO-sGC-cGMP axis stimulators on cardiac muscle, endothelial cells, and kidneys. Full article

Background/Objectives: Pulmonary hypertension is a progressive disease leading to right heart failure. One treatment strategy is to induce vasodilation via the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling pathway. There are currently two soluble guanylate cyclase stimulators on the market: Riociguat and vericiguat, with vericiguat having a longer half-life and needing to be taken only once a day. This study investigated whether the pharmacological differences between the drugs affect pulmonary vessels and airways. Methods: The effects of vericiguat and riociguat on pulmonary arteries, veins, and airways were studied using rat precision-cut lung slices (PCLS). Vessels were pretreated with endothelin-1 and airways with serotonin. In isolated perfused lungs (IPL), the effects of sGC stimulation on pulmonary artery pressure (PAP), airway resistance, inflammatory cytokine, and chemokine release were quantified. Results: Riociguat and vericiguat caused pulmonary artery dilation in PCLS. During IPL, riociguat was more effective than vericiguat in reducing PAP with a statistically significant reduction of 10%. Both drugs were potent bronchodilators in preconstricted airways (p < 0.001). Only vericiguat reduced airway resistance during IPL, as shown here for the first time. Both drugs significantly reduced IL-6 and IL-1ß levels, while riociguat also reduced VEGF-A and KC-GRO levels. Conclusions: Riociguat and vericiguat had three main effects in the two rat ex-vivo models: They dilated the pulmonary arteries, induced bronchodilation, and reduced inflammation. These properties could make sGC stimulators useful for treating diseases associated with endothelial dysfunction. In the future, vericiguat may provide an alternative treatment to induce bronchodilation in respiratory diseases. Full article

Primary pulmonary hypertension (PPH), now known as pulmonary arterial hypertension (PAH), has induced significant treatment breakthroughs in the past decade. Treatment has focused on improving patient survival and quality of life, and delaying disease progression. Current therapies are categorized based on targeting different pathways known to contribute to PAH, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5 inhibitors), prostacyclin analogs, soluble guanylate cyclase stimulators, and activin signaling inhibitors such as Sotatercept. The latest addition to treatment options is soluble guanylate cyclase stimulators, such as Riociguat, which directly stimulates the nitric oxide pathway, facilitating vasodilation. Looking to the future, advancements in PAH treatment focus on precision medicine involving the sub-stratification of patients through a deep characterization of altered Transforming Growth Factor-β(TGF-β) signaling and molecular therapies. Gene therapy, targeting specific genetic mutations linked to PAH, and cell-based therapies, such as mesenchymal stem cells, are under investigation. Besides prevailing therapies, emerging PH treatments target growth factors and inflammation-modulating pathways, with ongoing trials assessing their long-term benefits and safety. Hence, this review explores current therapies that delay progression and improve survival, as well as future treatments with curative potential. Full article

Anterior myocardial infarction is a critical condition with significant implications for cardiac function and patient prognosis. Despite advancements in reperfusion therapies, optimizing recovery during the early phases of myocardial infarction remains challenging. Anterior myocardial infarction can lead to substantial long-term effects on a patient’s health due to extensive damage to the heart muscle, particularly the left ventricle, impacting both quality of life and overall prognosis. Vericiguat, a soluble guanylate cyclase stimulator, has shown promise in heart failure, but its role in early anterior myocardial infarction has not yet been fully explored. By enhancing soluble guanylate cyclase activity, vericiguat may increase cyclic guanosine monophosphate production, leading to vasodilation, inhibition of platelet aggregation, and potential cardioprotective effects. Currently, treatment options for anterior myocardial infarction primarily focus on reperfusion strategies and managing complications. However, there is a critical need for adjunctive therapies that specifically target the pathophysiological changes occurring in the early phases of myocardial infarction. Vericiguat’s mechanism of action offers a novel approach to improving vascular function and myocardial health, potentially contributing to innovative treatment strategies that could transform the care and prognosis of patients with anterior myocardial infarction. Full article

Heart failure (HF) is a syndrome characterized by signs and symptoms resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptides or evidence of congestion. HF patients are classified according to left ventricular ejection fraction (LVEF). Worsening HF (WHF) is associated with increased short- and long-term mortality, re-hospitalization, and healthcare costs. The standard treatment of HF includes angiotensin-converting enzyme inhibitors, angiotensin receptor–neprilysin inhibitors, mineralocorticoid-receptor antagonists, beta-blockers, and sodium-glucose-co-transporter 2 inhibitors. To manage systolic HF by reducing mortality and hospitalizations in patients experiencing WHF, treatment with vericiguat, a direct stimulator of soluble guanylate cyclase (sGC), is indicated. This drug acts by stimulating sGC enzymes, part of the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) signaling pathway, regulating the cardiovascular system by catalyzing cGMP synthesis in response to NO. cGMP acts as a second messenger, triggering various cellular effects. Deficiencies in cGMP production, often due to low NO availability, are implicated in cardiovascular diseases. Vericiguat stimulates sGC directly, bypassing the need for a functional NO-sGC-cGMP axis, thus preventing myocardial and vascular dysfunction associated with decreased sGC activity in heart failure. Approved by the FDA in 2021, vericiguat administration should be considered, in addition to the four pillars of reduced EF (HFrEF) therapy, in symptomatic patients with LVEF < 45% following a worsening event. Cardiac rehabilitation represents an ideal setting where there is more time to implement therapy with vericiguat and incorporate a greater number of medications for the management of these patients. This review covers vericiguat’s metabolism, molecular mechanisms, and drug–drug interactions. Full article

This review delves into the most recent therapeutic approaches for pediatric chronic heart failure (HF) as proposed by the International Society for Heart and Lung Transplantation (ISHLT), which are not yet publicly available. The guideline proposes an exhaustive overview of the evolving pharmacological strategies that are transforming the management of HF in the pediatric population. The ISHLT guidelines recognize the scarcity of randomized clinical trials in children, leading to a predominance of consensus-based recommendations, designated as Level C evidence. This review article aims to shed light on the significant paradigm shifts in the proposed 2024 ISHLT guidelines for pediatric HF and their clinical ramifications for pediatric cardiology practitioners. Noteworthy advancements in the updated proposed guidelines include the endorsement of angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), and soluble guanylate cyclase (sGC) stimulators for treating chronic HF with reduced ejection fraction (HFrEF) in children. These cutting-edge treatments show potential for enhancing outcomes in pediatric HFrEF. Nonetheless, the challenge persists in validating the efficacy of therapies proven in adult HFrEF for the pediatric cohort. Furthermore, the proposed ISHLT guidelines address the pharmacological management of chronic HF with preserved ejection fraction (HFpEF) in children, marking a significant step forward in pediatric HF care. This review also discusses the future HF drugs in the pipeline, their mechanism of actions, potential uses, and side effects. Full article

Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor β (TGFβ)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFβ1-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGFβ1, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGFβ1-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFβ1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1β and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions. Full article

Heart failure with reduced ejection fraction is a chronic and progressive syndrome that continues to be a substantial financial burden for health systems in Western countries. Despite remarkable advances in pharmacologic and device-based therapy over the last few years, patients with heart failure with reduced ejection fraction have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Worsening heart failure episodes represent a critical event in the heart failure trajectory, carrying high residual risk at discharge and dismal short- or long-term prognosis. Recently, vericiguat, a soluble guanylate cyclase stimulator, has been proposed as a novel drug whose use is already associated with a reduction in heart failure-related hospitalizations in patients in guideline-directed medical therapy. In this review, we summarized the pathophysiology of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate cascade in patients with heart failure with reduced ejection fraction, the pharmacology of vericiguat as well as the evidence regarding their use in patients with HFrEF. Finally, tips and tricks for its use in standard clinical practice are provided. Full article