Guanylate Cyclase Stimulator Research Articles

Unstable heart failure: practical guidelines for avoiding frequent hospital admissions

Heart failure is the leading cause of hospital admissions in Germany. The prevention of hospitalizations due to heart failure has recently improved, encompassing guideline-based basic therapy, targeted medication escalation options, and structured outpatient care incorporating telemedicine. An early identification of parameters that precede or indicate acute heart failure is crucial. The term "worsening heart failure" is broader than the term "acute heart failure". Worsening heart failure includes patients identified through clinical examination, biochemical methods (especially natriuretic peptides), and imaging (echocardiography, chest X-ray, lung ultrasound, computed tomography, magnetic resonance imaging), and innovative cardiac telemonitoring. Early detection of worsening heart failure is only beneficial if followed by appropriate management that stabilizes heart failure, reduces mortality, and decreases hospital admissions and emergency contacts. Dedicated guidelines for the treatment of worsening heart failure are not yet available. It is recommended to start or up-titrate guideline-recommended medical therapy and additionally initiate treatment with the soluble guanylate cyclase stimulator Vericiguat in patients with heart failure with a reduced ejection fraction. Initiation and up-titration should begin during hospitalization and should be completed during careful follow-up within the first 6 weeks after discharge. This guide provides recommendations for the comprehensive and coordinated treatment of worsening heart failure, considering all these aspects which are crucial for improving patient outcomes.

Emerging therapies and new directions in the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe and progressive disease with limited survival prospects under currently available therapies. Since the 2022 edition of the European Society of Cardiology and European Respiratory Society guidelines on pulmonary hypertension, substantial clinical evidence has emerged, supporting a new treatment algorithm for PAH as presented at the 7th World Symposium on Pulmonary Hypertension 2024 and the following proceeding papers. Key updates include the introduction of sotatercept as a second-line therapy leading to a revised definition of maximal medical therapy now encompassing agents from four therapeutic groups (phosphodiesterase-5 inhibitors/soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin pathway agents, and sotatercept), instead of three (phosphodiesterase-5 inhibitors/soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin pathway agents). Other novelties include the elimination of a distinct pathway for patients with cardiopulmonary comorbidities in favor of an individualized approach, a reduction in the initial patient assessment risk categories from three to two, and a follow-up interval shortened from 3-6 months to 3-4 months post-treatment initiation. This review presents these advancements and emphasizes the need for their widespread implementation in clinical practice. At the end, we present new opportunities and challenges in the treatment of pulmonary arterial hypertension in eight Central and Eastern European countries.

Exploring Novel Therapeutics for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of pulmonary arteries. Dysregulated bone morphogenetic protein (BMP) signaling pathway contributes to the development of PAH, and pulmonary vasodilators including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostaglandins and soluble guanylate cyclase stimulators, dramatically improve the long-term prognosis. However, there still exist refractory patients who require continuous catecholamine support or lung transplantation, and the development of new treatment strategies targeting molecular mechanisms of PAH is highly anticipated. Sotatercept, a first-in-class activin signaling inhibitor, has recently been approved for the treatment of PAH, and it targets and restores an imbalance in activin-growth differentiation factor and BMP pathway signaling. In addition, treatment strategies targeting peroxisome proliferator-activated receptor-γ signaling, inflammatory and immune systems, DNA damage response and cellular senescence, and growth factor receptors including vascular endothelial growth factor and platelet-derived growth factor receptors, are being devised. In this review, we briefly summarize the recent advances in basic research paving the way for the development of more effective treatments for PAH and their potential in clinical therapeutic applications.

Assessment of cardiac reverse remodeling in patients with LV systolic dysfunction receiving vericiguat in addition to optimal GDMT

Abstract Background and Objective Vericiguat is a soluble guanylate cyclase stimulator which has demonstrated significant clinical and survival benefits in patient with heart failure and reduced ejection fraction (HFrEF) following acute decompensation. We present data on cardiac reverse remodeling assessed by echocardiography in ‘real-world’ patients receiving this therapy in addition to optimal guideline-directed medical therapy (GDM) for at least 6 months prior to initiation. Material and method Patients with a clinical indication for Vericiguat therapy were retrospectively analysed from a local registry between December 2022 and September 2023. A comprehensive echocardiography evaluation was performed at baseline (i.e. prior to initiation of this medication), and at 3 months after Vericiguat treatment. Results A total of 44 patients were included in this observational study, of which 32 patients were men (77.3%), and 10 patients were women (22.7%). With regards to baseline comorbidities, 17 patients had arterial hypertension, 12 patients had type-2 diabetes mellitus, 21 patients had hypercholesterolaemia, and 6 patients were newly diagnosed with HFrEF. The aetiology of HFrEF was ischaemic in 25 patients, and non-ischaemic in 19 patients. A total of 40 patients were on ARNI therapy prior to initiation of Vericiguat, 40 patients were on beta-blockers, 39 patients were on MRAs, 44 patients were on SGLT2-inhibitors, 18 patients were of loop diuretics, 15 patients had an ICD in situ, and 6 patients had a CRT device implanted. The mean initial LVEF was 31%, with a mean initial end-diastolic volume (EDV) of 178 mL. At 3-month follow-up, the mean LVEF was 39%, which represents an improvement of 9 percentage points; the mean EDV at 3-month follow-up was reduced up to 157 mL. Conclusions Vericiguat therapy may exhibit additional anti-remodelling benefits in patients with HFrEF when in combination with optimal GDMT in ‘real-world’ populations. Large randomized and prospective trials are needed to explore this hypothesis.

Vericiguat for heart failure with reduced ejection fraction (HFrEF): A review of its potential benefits in Pakistan

Heart failure (HF) is categorized by left ventricular ejection fraction (LVEF) into three groups. HF with reduced ejection fraction (HFrEF) is one of these groups characterized by the heart’s inability to pump sufficient blood to meet the body’s needs, resulting from the left ventricle’s impaired ability to contract effectively. The Canadian Cardiovascular Society (CCS) guidelines recommend vericiguat for hospitalized patients experiencing worsening symptoms of HFrEF. This article reviews vericiguat’s efficacy and potential benefits in Pakistani patients with HFrEF. A literature search from 2013 to 2024 was conducted using PubMed, ScienceDirect, and Google Scholar, employing keywords such as guidelines, heart failure, Pakistan, and reduced ejection fraction. Soluble guanylate cyclase (sGC) stimulators, like vericiguat, have shown benefits in patients with left ventricular hypertrophy and fibrosis by reducing afterload through vasodilation. Vericiguat (2.5 – 10 mg taken orally once daily) shows promise in reducing cardiovascular mortality and hospitalization in adults with LVEF ≤45%. Vericiguat may alleviate Pakistan’s growing cardiovascular disease burden. Expedited access to this innovative therapy can be achieved through collaborative efforts among policymakers, healthcare authorities, and international research centers, potentially reducing hospitalization rates in Pakistani HFrEF patients.

Soluble guanylate cyclase stimulators and activators as potential antihypertensive drugs.

Poor blood pressure control in treated patients with hypertension is an important topic in the field of hypertension, and an unmet need for new therapeutic drugs remains. Soluble guanylate cyclase (sGC), a key signal transduction enzyme responsible for vasodilation, has attracted increasing interest as a therapeutic target in various cardiovascular diseases. Two different sGC agonists, sGC stimulators and activators, can increase its enzymatic activity in reduced and oxidized/apo forms, respectively. With some sGC agonists being already in clinical use, drugs in this category are expected to become new therapeutic agents for various conditions, including hypertension. In this review, we summarize the current knowledge on the antihypertensive effects of sGC agonists in various preclinical studies involving animal models of spontaneous hypertension, salt-sensitive hypertension, nitric oxide-deficient hypertension, renin-angiotensin-aldosterone system-dependent hypertension, malignant hypertension, metabolic syndrome, renoprival hypertension, renovascular hypertension, drug-induced hypertension, pregnancy hypertension, and treatment-resistant hypertension. Our compilation provides a comprehensive rationale for advancing the clinical development of sGC agonists for the treatment of hypertension.

Novel Therapies for Right Ventricular Failure.

Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF. This review aims to reassure about the progress in RVF treatment by exploring the potential of contemporary therapies for heart failure, including angiotensin receptor andneprilysin inhibitors, sodium-glucose co-transporter 2 inhibitors, and soluble guanylate cyclase stimulators, which may be beneficial for treating RV failure, particularly when associated with left heart failure. Additionally, it examines novel therapies currently in the pipeline. Over the past decade, a new wave of RVF therapies has emerged, both pharmacological and device-centered. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation have shown significant promise in preclinical studies. There is also a burgeoning interest in the potential of epigenetic modifications as therapeutic targets for RVF. Undoubtedly, a deeper understanding of the mechanisms underlying RV failure, both with and without pulmonary hypertension, is urgently needed. This knowledge is not just a theoretical pursuit, but a crucial step that could lead to the development of pharmacological and cell-based therapeutic options that directly target the RV and pulmonary vasculature, aligning with the principles of precision medicine.

Vericiguat improves cardiac remodelling and function in rats with doxorubicin-induced cardiomyopathy.

Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has been demonstrated effective in improving prognosis of patients with heart failure with reduced ejection fraction. However, there are limited data concerning the effect of vericiguat in patients with doxorubicin (DOX)-induced cardiomyopathy (DIC). In this study, we investigated the effects of vericiguat on cardiac structure and function in rats with DIC as well as their potential mechanisms of action. DIC rats were established by intraperitoneal injection of DOX (1mg/kg) twice a week for 6weeks, followed by intragastric administration of vericiguat 1mg/kg/day or an equal volume of normal saline for 8weeks. Cardiac histology and function, circulating levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP), nitric oxide (NO), and oxidative indices, as well as myocardial cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling, oxidative and apoptosis-associated protein were measured. Compared with the control group, rats treated with DOX exhibited significantly increased heart size, reduced systolic function and elevated plasma levels of NT-proBNP. Histological findings revealed myocardial cell atrophy, fibrosis and apoptosis. Vericiguat treatment effectively reversed DOX-induced cardiac remodelling and improved systolic function. Mechanistically, Vericiguat attenuated the inhibitory effects of DOX on the myocardial cGMP-PKG axis and nuclear factor erythroid 2-related factor 2 (Nrf2) protein, thereby alleviating oxidative stress and apoptosis. Vericiguat improved cardiac remodelling and contractile function in rats with DIC through upregulation of cGMP-PKG signalling and inhibition of oxidative stress and myocardial apoptosis.

Clinical profile of an unselected population with heart failure treated with vericiguat in real life: differences with the VICTORIA trial.

Vericiguat, an oral stimulator of soluble guanylate cyclase, reduces cardiovascular mortality and hospitalisations in patients with heart failure (HF) and reduced ejection fraction, as demonstrated in the VICTORIA trial. This study assessed the real-world use of vericiguat. This cross-sectional, prospective and multicenter registry (VERISEC) included 776 patients from 43 centres in Spain between December 2022 and October 2023. Of these patients, 79.6% were male, with a mean age of 72.4 (SD:8.7) years. Patients in VERISEC were older and had more comorbidities (diabetes, advanced chronic kidney disease) compared to VICTORIA, with 20% having an estimated glomerular filtration rate below 30 ml/min. They also had higher natriuretic peptide levels [NT-proBNP: 3551 (IQR: 1,675.9, 7,054.0)] pg/ml. Most patients (79.8%) started vericiguat after HF decompensation within the previous three months, with high use of loop diuretics (with an average dose of 65 mg/day) and implanted devices (50%). Sixty percent of patients were on quadruple therapy, with a higher use of sodium-glucose co-transporter 2 inhibitors compared to the VICTORIA trial. Despite the more severe disease in the VERISEC cohort, the implementation of guideline-directed medical therapy was greater than in VICTORIA, although vericiguat was initiated at lower blood pressure levels. Patients in the VERISEC registry had more severe illness and higher comorbidities compared to those in the VICTORIA, despite receiving optimised treatments. Further research is needed to identify which patients may benefit the most from vericiguat treatment.

Efficacy and Safety of Sotatercept in Pulmonary Arterial Hypertension: A Systematic Review

Context: Pulmonary arterial hypertension (PAH) is characterized by the narrowing and remodeling of small pulmonary arteries, resulting from an imbalance in signaling pathways that regulate cell proliferation. Current therapeutic strategies for PAH target specific pathways to enhance pulmonary hemodynamics, including soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostacyclin pathway modulators. Sotatercept emerges as a promising therapeutic option that targets the underlying mechanism of PAH by improving the integrity of the endothelial layer of pulmonary arteries, promoting cellular proliferation, and alleviating vascular dysfunction. Objectives: This study systematically aims to review existing literature on the efficacy and safety of sotatercept in treating PAH. Methods: A comprehensive search was conducted across five online databases (PubMed, Scopus, Web of Science, Embase, and Google Scholar) to identify relevant studies. Original studies with human participants that investigated the efficacy and safety of sotatercept in patients with PAH were included. The primary outcomes assessed included clinical parameters such as pulmonary artery wedge pressure (PAWP), pulmonary vascular resistance (PVR), mean right atrial pressure (mRAP), mean pulmonary artery pressure (mPAP), 6-minute walk distance (6MWD), and improvements in World Health Organization functional class (WHO FC) over follow-up periods of up to 24 weeks. Additionally, adverse events such as thrombocytopenia, bleeding, headaches, telangiectasia, increased blood pressure, nausea, diarrhea, fatigue, and epistaxis were evaluated. Results: After screening, nine studies involving a total of 323 participants were included in the review. The analysis revealed that sotatercept significantly reduced PVR and led to notable improvements in 6MWD and NT-proBNP levels among patients. The treatment was well-tolerated across various dosages, with all evaluated adverse events being manageable. Conclusions: The findings indicate that sotatercept is an effective therapeutic intervention for patients with PAH, significantly reducing PVR while enhancing exercise capacity and improving biomarkers of heart failure. The adverse effects associated with sotatercept were generally mild and manageable. The results support the potential of sotatercept as a valuable addition to the current treatment landscape for PAH. Further studies are warranted to comprehensively evaluate all related outcomes and potential adverse events associated with this therapy.

Chronic Thromboembolic Pulmonary Hypertension Drug Treatment

The main treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is radical surgery, pulmonary thromboendarterectomy (PEA). However, about 40% of patients with CTEPH are inoperable due to distal pulmonary vascular lesions or the severity of hemodynamic disorders. Almost 30% of patients with CTEPH experience persistent or recurrent pulmonary hypertension after surgery, that requires a drug treatment with PAH-specific drugs. This review presents current data on the use of targeted therapy in patients with CTEPH. The review addresses the place, indications, and the evidence base for using the main groups of specific drugs, including stimulators of soluble guanylate cyclase, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, and prostacyclin analogues.

Group 5 PH: Diagnosis and Management of Pulmonary Hypertension in Patients with a Focus on Chronic Haemolytic Diseases in the UAE

Group 5 pulmonary hypertension (PH) encompasses PH associated with chronic haemolytic diseases, which is the major cause of morbidity and mortality in patients. The prevalence of PH is notably high in sickle cell disease (SCD), thalassemia, hereditary spherocytosis, and paroxysmal nocturnal haemoglobinuria. Pulmonary symptoms are common with haematological diseases; therefore, systematic evaluation of patients who are at increased risk of developing PH is vital. Evaluation by NT-pro BNP and echocardiography (ECHO) is essential for early referral to PH centres. Right heart catheterisation in patients with haemoglobinopathies is recommended in making a diagnosis of precapillary PH. A V/Q scan should be considered in the evaluation of dyspnoea for detecting thrombotic events in SCD. Once haemolytic disease is confirmed as the cause of PH, the underlying cause of haemolytic disease is managed with an emphasis on the reversal of hypoxaemia. Evidence suggests that hydroxyurea can treat patients with haemolytic disease and PH, but exchange blood transfusions are used as an alternative when patients are unresponsive to hydroxyurea. Riociguat, a soluble guanylate cyclase stimulator, has been found to be safe and effective in sickle-cell-related pulmonary arterial hypertension. Novel drugs like voxelotor (FDA approved) and crizanlizumab have shown their efficacy in patients with SCD and vaso-occlusive crisis. Hence, this study emphasises the systematic evaluation of patients for early diagnosis and early positioning of novel agents to prevent PH associated with chronic haemolytic diseases, particularly SCD.

New and future heart failure drugs.

In the past decade, our understanding of heart failure pathophysiology has advanced significantly, resulting in the development of new medications such as angiotensin-neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors and oral soluble guanylate cyclase stimulators. Backed by positive findings from large randomized controlled trials, recommendations for their use were recently included in the 2022 AHA/ACC/HFSA guidelines and 2023 ESC guidelines for management of heart failure. Promising drugs for future heart failure treatment include agents that modulate the neurohormonal system, vasodilators, anti-inflammatory drugs, mitotropes, which improve deranged energy metabolism of the failing heart, and myotropes, which increase cardiac contractility by affecting cardiac sarcomere function. Here, we discuss these new and future heart failure drugs. We explain their mechanisms of action, critically evaluate their performance in clinical trials and summarize the clinical scenarios in which the latest guidelines recommend their use. This Review aims to offer clinicians and researchers a comprehensive overview of novel therapeutic classes in heart failure treatment.

Pathway to care, treatment and disease burden of pulmonary arterial hypertension: a real-world survey of physicians and patients in Latin America

ObjectivesTo investigate clinical characteristics, symptom profile, testing practices, treatment patterns and quality of life (QoL) among patients with pulmonary arterial hypertension (PAH) in Latin America.DesignData from the Adelphi Real World...

A Phase II study of avenciguat, a novel soluble guanylate cyclase activator, in patients with systemic sclerosis: Study design and rationale of the VITALISScE™ study.

Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc). However, the efficacy of soluble guanylate cyclase stimulators may be reduced under conditions of hypoxia and oxidative stress. Soluble guanylate cyclase activators have the potential to overcome this limitation. This paper describes the study design of VITALISScE™, a Phase II clinical trial assessing the efficacy, safety and tolerability of avenciguat, a novel soluble guanylate cyclase activator in patients with active systemic sclerosis at risk of progression. The VITALISScE™ study (NCT05559580) is evaluating the action of avenciguat on all three aspects of systemic sclerosis pathophysiology. The primary endpoint is the rate of decline in forced vital capacity (mL) over 48 weeks. Secondary endpoints include absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire Disability Index score and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints include a composite assessment of Raynaud's phenomenon, digital ulcer burden, functional outcomes and quality of life, safety, pharmacokinetics, and biomarkers associated with systemic sclerosis and the mechanism of action of avenciguat. VITALISScE™ is an ongoing, multicentre (180 sites; 38 countries), placebo-controlled, double-blind, parallel-group, Phase II clinical study. Recruitment is currently ongoing. The VITALISScE™ study is assessing the efficacy, safety and tolerability of avenciguat in patients with active systemic sclerosis at risk of progression. Results will inform further development of avenciguat. VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580).

Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial.

In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy. The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo. VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

In-hospital initiation of Vericiguat and short-term cardiovascular function improvement in heart failure patients with worsened renal function

Abstract Background and Aims Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for treating heart failure (HF) with reduced ejection fraction (HFrEF). This study aims to assess the short-term improvement in cardio-function resulting from in-hospital initiation of Vericiguat among patients with chronic kidney dysfunction (CKD), utilizing real-world data from a single-center experience in western China. Method Data were obtained from the Biobank of our hospital, spanning from January 2023 to December 2023. A total of 213 HF patients with Vericiguat initiation were screened for eligibility. Echocardiography was employed to evaluate cardio-function after 1- and 3-month short-term follow-up in each patient. Statistical analyses were conducted using one-way ANOVA (followed by Geisser-Greenhouse correction and Tukey’s multiple comparison) to assess significance between different timepoints. Results Among the 213 patients randomized in this study, baseline characteristics were compared based on estimated glomerular filtration rate (eGFR) ≤ 30 (worsened renal function group, WRF, n = 20) and >30 mL/min/1.73 m2 (n = 193). No significant differences were observed in age, gender, and other biochemical parameters expect hemoglobin and creatine between the two groups (Table 1). Analysis of cardiac function after 1- and 3-month follow-up revealed a promising increase in left ventricular ejection fraction (EF) (37.2% vs. 43.9%, Mean diff -6.7, 95% CI -12.78 to -0.62, p = 0.03), fractional shortening (FS) (20.9% vs. 25.3%, Mean diff -4.42, 95% CI -8.57 to -0.27, p = 0.04), and a significant decrease in left ventricular end-diastolic dimension (LVEDD) (65.0mm vs. 60.6mm, Mean diff 4.35, 95% CI 0.33 to 8.38, p = 0.03) after 3-month follow-up compared to Vericiguat initiation in WRF patients. However, no significant changes were observed between the beginning and 1-month follow-up in echocardiographic measurements (Figure 1). Conclusion In this real-world single-center study, Vericiguat demonstrated effectiveness in short-term improvement of cardiac function among HF patients with worsened renal function. The long-term efficacy in reducing major cardiovascular events in this subgroup, based on real-world experience, warrants further exploration.

Comparison of sGC activator and sGC stimulator in 5/6 nephrectomized rats on high-salt-diet.

Soluble guanylate cyclase (sGC) stimulators and activators are known to enhance kidney function in various models of chronic kidney disease (CKD) by increasing cyclic guanosine monophosphate (cGMP). Their differential effects on CKD progression, particularly under conditions of oxidative stress, remain unexplored by direct comparative studies. We conducted a side-by-side comparison using 5/6 nephrectomized rats on a high salt diet (5/6Nx+HSD) to evaluate the efficacy of the sGC stimulator BAY 41-8543 and the sGC activator BAY 60-2770 in CKD progression. BAY 41-8543 (1mg/kg; twice daily) and BAY 60-2770 (1mg/kg; once daily) were administered by gavage for 11 weeks. The 5/6Nx+HSD model led to increased plasma creatinine, proteinuria, and blood pressure. Both BAY 41-8543 and BAY 60-2770 significantly reduced systolic and diastolic blood pressure to a similar extent but did not improve renal function parameters. Notably, BAY 60-2770 reduced renal fibrosis, including interstitial fibrosis and glomerulosclerosis, whereas BAY 41-8543 did not. These antifibrotic effects of BAY 60-2770 were independent of blood pressure reduction. Proteomic analysis revealed that BAY 60-2770 corrected the upregulation of 9 proteins associated with apoptosis and fibrosis, including Caspase-3, MKK6 (Mitogen-Activated Protein Kinase Kinase 6), Prdx5 (Peroxiredoxin-5), in the 5/6Nx+HSD group. In contrast, BAY 41-8543 had no significant impact on these proteins. sGC activators were more effective than sGC stimulators in reducing renal fibrosis in 5/6 nephrectomized rats on a high salt diet, and this effect was due to modulation of apoptosis-associated proteins beyond the control of blood pressure.

An Investigation of Pharmacokinetic Interaction of Vericiguat with Apigenin based on a Newly Developed Ultra-performance Liquid Chromatography-tandem Mass Spectrometry Assay.

Vericiguat, as a new stimulator of soluble guanylate cyclase (s- GC), was recently approved as a first-in-class treatment for reducing risks in patients with ejection fraction less than 45 percent and heart failure (HF) in the USA. The main aim of the present experiment was to establish an acceptable, sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentration levels of vericiguat in rats, and to further evaluate the effect of apigenin on the metabolism of vericiguat in vivo. In sample processes, acetonitrile was finally chosen for quickly precipitating protein. The levels of vericiguat in plasma were analyzed by a Xevo TQ-S triple quadrupole tandem mass spectrometry (Milford, MA, USA) in a positive ion mode. The scope of the calibration standard for vericiguat ranged from 0.5 to 1000 ng/mL, where a great linearity was acceptable. The lower limit of quantification (also called LLOQ) of vericiguat presented the sensitivity of this assay was evaluated as low as 0.5 ng/mL. Additionally, selectivity, accuracy and precision, extraction recovery, matrix effect, and stability were all verified. Subsequently, this approach also supported to assess the plasmatic concentrations of vericiguat from an interaction survey on herb-- drug, in which oral administration of apigenin (20 mg/kg) obviously increased the plasmatic levels of vericiguat and altered the pharmacokinetics of vericiguat in rats. These results would help us to further understand the pharmacokinetic properties of vericiguat when co-administration with apigenin, and to avoid unexpected clinical risks in the future.

Indian Experience with Vericiguat: A Review Based upon Case Series.

Heart failure (HF) is a condition that can result in repeated hospitalizations every year and can result in worsening HF (WHF). Although current pharmacological treatment for HF is fairly effective, there is a need to lower the residual risk of cardiovascular events and hospitalizations. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, a new entrant, seems to present a promising therapeutic option for HF with signs of worsening, and early initiation of this therapy may be beneficial in certain patient profiles. This article explores the potential benefits of early vericiguat initiation in four patient profiles who presented with WHF.