Guanylate Cyclase Stimulator Research Articles

Serum from Men with the Severe Form of COVID-19 Impairs the Nitric Oxide Signaling Pathway in Isolated Corpus Cavernosum from Mice: An In Vitro Study

Introduction. Erectile dysfunction (ED) is characterized by the inability to achieve and/or maintain an erection during sexual activity. Vascular-related diseases such as obesity, diabetes, aging, and hypertension are known risk factors that increase the prevalence of ED. The viral infection caused by SARS-CoV-2, the etiological agent of COVID-19, can evolve into mild to severe forms. Patients with comorbidities such as diabetes and obesity present a more severe state of the disease. The cytokine storm and reactive oxygen species associated with COVID-19 can lead to progressive systemic inflammation and vascular dysfunction. This study is aimed at assessing the in vitro effects of serum obtained from unvaccinated men who had the severe form of COVID-19 in isolated corpus cavernosum (CC) from healthy mice. Methods. Concentration-response curves to endothelium-dependent and endothelium-independent substances were carried out in isolated CC from mice after being incubated (3 hours) with serum obtained from patients with and without (control group) the severe form of COVID-19. qRT-PCR and western blotting were also carried out. Results. The relaxing responses induced by acetylcholine (ACh), a nitric oxide donor (sodium nitroprusside), soluble guanylate cyclase (sGC) stimulator (BAY 63-2521), and phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) were significantly reduced in CC incubated with COVID-19 serum when compared with CC incubated with the control serum. Nonetheless, the relaxation induced by the sGC activator BAY 58-2667 was unaffected in CC stimulated with the COVID-19 serum. The coincubation of control or COVID-19 serum with a free radical scavenger (PEG-SOD; 150 UI/mL, 3 hours) significantly improved the relaxation induced by ACh. On the other hand, catalase did not improve ACh-induced relaxation in CC incubated with the sera. The gene expression for PDE5 and NADPH oxidase type 4 was increased in CC stimulated with COVID-19 serum in comparison to tissues stimulated with the control serum. The protein expression for sGC subunits was similar in both groups. Conclusion. Serum obtained from unvaccinated men who presented the severe form of COVID-19 impaired the relaxation induced by cyclic guanosine monophosphate-accumulating substances in CC from mice.

Chronic heart failure: the role of di vericiguat.

The introduction of multiple new pharmacological agents over the past three decades in the field of heart failure with reduced ejection fraction (HFrEF) has led to reduced rates of mortality and hospitalizations, and consequently, the prevalence of HFrEF has increased, and up to 10% of patients progress to more advanced stages, characterized by high rates of mortality and hospitalizations and poor quality of life. Vericiguat, a novel oral soluble guanylate cyclase stimulator, has proved effective in patients with HFrEF who had recently been hospitalized or had received intravenous diuretic therapy. In these patients, vericiguat reduced the primary outcome of death from cardiovascular causes or first hospitalization for heart failure in comparison with placebo. By reducing hospital admissions in a population at a very high risk of re-hospitalization, vericiguat might have a positive impact on healthcare costs for the management of HFrEF.

Refined risk stratification, current treatment, and new therapeutic approaches in pulmonary arterial hypertension.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for pulmonary hypertension have introduced arefined risk stratification to guide both initial and subsequent treatment of pulmonary arterial hypertension (PAH). The risk stratification at PAH diagnosis still comprises three risk categories (low, intermediate, high) and lists some new parameters. As the estimated 1‑year mortality is more than 20% in high-risk patients after diagnosis, an initial triple-combination therapy including parenteral prostacyclin analogues is recommended for this group. All other patients should receive adual-combination therapy with an endothelin receptor antagonist and aphosphodiesterase‑5 inhibitor. However, this approach of initial combination therapy is only recommended for classic PAH, while monotherapy followed by regular follow-up and individualized therapy should be used for patients with cardiopulmonary comorbidities. For PAH patients without cardiopulmonary comorbidities, it is recommended to assess their risk at follow-up with anew 4‑strata classification, where the intermediate-risk group is split on the basis of three noninvasive parameters. Importantly, changes from intermediate-high to intermediate-low risk have been shown to be associated with abetter prognosis. In addition, the recommendations on treatment escalation became more precise with the addition of aprostacyclin receptor agonist or switching aphosphodiesterase‑5 inhibitor to asoluble guanylate cyclase stimulator for intermediate-low risk and proceeding to triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk. With sotatercept, the first non-vasodilator PAH treatment will become available in the near future to further enrich our treatment options for this chronic and still severe disease.

Soluble Guanylate Cyclase Activators and Stimulators in Patients with Heart Failure

This review sought to summarize the current emerging soluble guanylate cyclase activators and stimulators in patients with heart failure, both heart failure with reduced and preserved ejection fraction, to provide a reference for soluble guanylate cyclase activators and stimulators discovery. Heart failure is a common disease with considerable morbidity, hospitalization, and mortality Soluble guanylate cyclase is a key enzyme in the nitric oxide signaling pathway and has attracted rapidly growing interest as a therapeutic target in heart failure. Currently, several soluble guanylate cyclase agonists are in clinical development. Cinaciguat and praliciguat have shown no clear clinical benefit in patients with heart failure in clinical trials. Riociguat increased the 6-min walk distance, cardiac index, and stroke volume index as well as decreased N-terminal pro-B-type natriuretic peptide. Although these populations cover nearly every range of ejection fractions, these were not clinical trials directly in patients with heart failure but were designed in patients with pulmonary hypertension. Vericiguat is recommended in the latest American guideline for patients with heart failure with reduced ejection fraction; however, it gets mixed results in patients with heart failure with preserved ejection fraction. To date, only vericiguat reduces the composite of death from cardiovascular causes or first hospitalization for heart failure in patients with heart failure with reduced ejection fraction and riociguat might improve clinical symptoms and quality of life in patients with heart failure, both heart failure with reduced and preserved ejection fraction. We need more exploration about soluble guanylate cyclase activators and stimulators in patients with heart failure.

Pharmacological effects of a new soluble guanylate cyclase stimulator in experimental pulmonary arterial hypertension

Aim. To assess the effect of an indolinone derivative (2-[2-[(5RS)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidine-2yliden]-2-cyanoethylidene]-1H-indole-3(2H)-one (codename – GRS) on right ventricular contractility, endothelial vasodilator function, and histologic changes in the lungs and heart in a rat model of monocrotaline-induced pulmonary hypertension.Materials and methods. Pulmonary arterial hypertension (PAH) was induced in Wistar rats by a single subcutaneous administration of monocrotaline at a dose of 60 mg / kg. Starting from day 15 after PAH induction, the rats received either GRS at a dose of 10 mg / kg or riociguat at a dose of 1 mg / kg orally once a day. Blood pressure in the right ventricle, right ventricular weight, endothelial vasodilator function, and the histologic structure of the lungs and heart were studied after the last administration of test substances.Results. Twenty-eight days after monocrotaline administration, the rats developed PAH, as shown by the increase in the maximal blood pressure in the right ventricle and the right ventricular weight / total heart weight ratio. GRS after multiple administration reduced the maximal blood pressure in the right ventricle, had no significant effect on its contractility, improved endothelial vasodilator function, and normalized blood pressure. Riociguat had a hypotensive effect and did not alleviate endothelial dysfunction in experimental PAH.Conclusion. The indolinone derivative GRS and riociguat, both soluble guanylate cyclase stimulators, lowered blood pressure in the right ventricle. GRS also alleviated endothelial dysfunction in animals with experimental PAH.

Cardiac Reverse Remodeling in Ischemic Heart Disease with Novel Therapies for Heart Failure with Reduced Ejection Fraction.

Despite the improvements in the treatment of coronary artery disease (CAD) and acute myocardial infarction (MI) over the past 20 years, ischemic heart disease (IHD) continues to be the most common cause of heart failure (HF). In clinical trials, over 70% of patients diagnosed with HF had IHD as the underlying cause. Furthermore, IHD predicts a worse outcome for patients with HF, leading to a substantial increase in late morbidity, mortality, and healthcare costs. In recent years, new pharmacological therapies have emerged for the treatment of HF, such as sodium-glucose cotransporter-2 inhibitors, angiotensin receptor-neprilysin inhibitors, selective cardiac myosin activators, and oral soluble guanylate cyclase stimulators, demonstrating clear or potential benefits in patients with HF with reduced ejection fraction. Interventional strategies such as cardiac resynchronization therapy, cardiac contractility modulation, or baroreflex activation therapy might provide additional therapeutic benefits by improving symptoms and promoting reverse remodeling. Furthermore, cardiac regenerative therapies such as stem cell transplantation could become a new therapeutic resource in the management of HF. By analyzing the existing data from the literature, this review aims to evaluate the impact of new HF therapies in patients with IHD in order to gain further insight into the best form of therapeutic management for this large proportion of HF patients.

New Generation of sGC Stimulators: Discovery of Imidazo[1,2-a]pyridine Carboxamide BAY 1165747 (BAY-747), a Long-Acting Soluble Guanylate Cyclase Stimulator for the Treatment of Resistant Hypertension.

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

Correction to: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

HomeCirculationVol. 147, No. 14Correction to: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines Originally published3 Apr 2023https://doi.org/10.1161/CIR.0000000000001142Circulation. 2023;147:e674This article corrects the following2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice GuidelinesIn the article by Heidenreich et al, “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines,” which published ahead of print on April 1, 2022, and appeared in the May 3, 2022, issue of the journal (Circulation. 2022;145:e895–e1032. doi: 10.1161/CIR.0000000000001063), a correction was needed.On page e938, in Table 14, under section “7.3.8. GDMT Dosing: Sequencing and Uptitration,” digoxin was classified incorrectly as a soluble guanylate cyclase stimulator. A heading titled “Cardiac glycoside” was added above digoxin.This correction has been made to the current online version of the article, which is available at: https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063.FootnotesCirculation is available at www.ahajournals.org/journal/circ Previous Back to top Next FiguresReferencesRelatedDetailsRelated articles2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice GuidelinesPaul A. Heidenreich, et al. Circulation. 2022;145:e895-e1032 April 4, 2023Vol 147, Issue 14 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIR.0000000000001142PMID: 37011077 Originally publishedApril 3, 2023 PDF download Advertisement

The first validated stability-indicating HPLC/DAD method for quantitation of Vericiguat in its pharmaceutical formulation; Application to degradation kinetic studies

The stability of innovative drug formulations and the development of appropriate stability-indicating methods remain major focuses of recent pharmaceutical analysis. In the present study, an efficient stability-indicating HPLC-DAD technique has been described and validated for the determination of Vericiguat (VER); a novel oral soluble guanylate cyclase (sGC) stimulator used in heart failure. VER's stability under various stress conditions was examined. It was shown that VER was sensitive to alkaline, oxidative and thermal degradation. Mass spectrometry (MS) in electrospray ionization mode was performed to figure out the structure of the alkaline and oxidative degradation products. Efficient separation of VER and its induced degradation products was accomplished using isocratic elution mode on the Inertsil ODS-C18 column. The mobile phase composed of water: acetonitrile (70:30 v/v) with 0.1% O-phosphoric acid; pH was adjusted to 2.22 and a flow rate of 0.80 mL/min. VER was detected at 332 nm over a concentration range of 2.00–20.00 μg/mL. The retention time was 4.500 ± 0.005 min and the correlation coefficient was 0.9996. Following the International Conference of Harmonization's guidelines, the analysis was validated to be specific, fast, simple, precise and accurate for utilization in routine analysis and quality control of VER in its pharmaceutical formulation. Additionally, the suggested technique was expanded to investigate the kinetics of alkaline, oxidative and dry heat degradation.

Vericiguat for the treatment of heart failure with reduced ejection fraction

ABSTRACT Introduction Despite significant therapeutic advancements in heart failure with reduced ejection fraction (HFrEF), the residual risk of all-cause mortality and hospitalizations remains high among patients with HFrEF. Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator which was approved by the US Food and Drug administration (FDA) in January 2021 for use in patients with symptomatic chronic HF and an ejection fraction less than 45% following a hospitalization for HF or the need for outpatient intravenous diuretics. Areas covered We provide a concise review of the pharmacology, clinical efficacy, and tolerability of vericiguat in HFrEF. We also discuss the role of vericiguat in current clinical practice. Expert opinion Vericiguat reduces the risk of cardiovascular mortality or HF hospitalizations by an absolute event-rate reduction of 4.2 events per 100 patient-years with a number needed to treat of 24 patients, on a background of guideline-directed medical therapy. Almost 90% of the patients with HFrEF were adherent to the 10 mg dose of vericiguat in the VICTORIA trial with a favorable tolerability and safety profile. Considering the high residual risk that persists in HFrEF, vericiguat has a role to improve outcomes among patients with worsening HFrEF.

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis.

During the onset of liver fibrosis, capillarized liver sinusoidal endothelial cells (LSECs) limit substance exchange between the blood and the Disse space, further accelerating hepatic stellate cell (HSCs) activation and fibrosis progression. Limited accessibility of therapeutics to the Disse space is often overlooked and remains a major bottleneck for HSCs-targeted therapy in liver fibrosis. Here, an integrated systemic strategy for liver fibrosis treatment is reported, utilizing pretreatment with the soluble guanylate cyclase stimulator, riociguat, followed by insulin growth factor 2 receptor-mediated targeted delivery of the anti-fibrosis agent, JQ1, via peptide-nanoparticles (IGNP-JQ1). The riociguat reversed the liver sinusoid capillarization to maintain a relatively normal LSECs porosity, thus facilitating the transport of IGNP-JQ1 through the liver sinusoid endothelium wall and enhancing the accumulation of IGNP-JQ1 in the Disse space. IGNP-JQ1 is then selectively taken up by activated HSCs, inhibiting their proliferation and decreasing collagen deposition in the liver. The combined strategy results in significant fibrosis resolution in carbon tetrachloride-induced fibrotic mice as well as methionine-choline-deficient-diet-induced nonalcoholic steatohepatitis (NASH) mice. The work highlights the key role of LSECs in therapeutics transport through the liver sinusoid. The strategy of restoring LSECs fenestrae by riociguat represents a promising approach for liver fibrosis treatment.

Atrophy signaling pathways in respiratory and limb muscles of guinea pigs exposed to chronic cigarette smoke: role of soluble guanylate cyclase stimulation.

Skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) is characterized by a significant reduction in muscle strength and endurance. Preclinical studies show that stimulation of the soluble guanylate cyclase (sGC)-cGMP pathway attenuates muscle mass loss and prevents cigarette smoke-induced oxidative stress, indicating that pharmacological activation of the guanylyl cyclase pathway in COPD may provide a beneficial therapeutic strategy that reaches beyond the lung. In this study, conducted in an animal model of COPD, we first set out to assess the effect of cigarette smoke (CS) on biomarkers of muscle fatigue, such as protein degradation and its transcriptional regulation, in two types of muscles with different energy demands, i.e., the diaphragm and the gastrocnemius muscle of the limbs. Second, we evaluated the administration of an sGC stimulator on these markers to study the potential efficacy of such treatment in the recovery of skeletal muscle function. Exposure to CS led to weight loss, which was associated in the gastrocnemius with increased levels of proteolytic markers of muscle atrophy (MURF-1, Atrogin-1, proteasome C8 subunit 20 s, and total protein ubiquitination), whereas the size of fast-twitch muscle fibers decreased significantly. Long-term treatment with the sGC stimulator BAY 41-2272 resulted in a significant reduction in gastrocnemius levels of the aforementioned proteolytic markers, concomitant with a weight recovery and increased cGMP levels. Remarkably, levels of some of the analyzed biomarkers differed between respiratory and limb muscles. In conclusion, targeting sGC might exert beneficial effects on muscle alterations in patients with COPD.

Новое в лечении сердечной недостаточности: верицигуат

The author reviews the pharmacological properties and clinical trials of vericiguate, a stimulant of soluble guanylate cyclase, that is intended for use in patients with chronic heart failure. The new medicine alleviates unfavorable effects of endothelial dysfunction and other disorders associated with a deficiency of bioavailable nitric oxide and suppressed activity of soluble guanylate cyclase. The efficacy of vericiguate in chronic heart failure with a reduced ejection fraction was established in clinical trials SOCRATES-REDUCED and VICTORIA.

Oligosaccharides from Human Milk Block Binding and Activity of the Escherichia coli Heat-Stable Enterotoxin (STa) in T84 Intestinal Cells , ,

Enterotoxin-producing Escherichia coli are major causes of pediatric diarrhea in developing countries. The heat-stable enterotoxin of Escherichia coli (STa) causes diarrhea by virtue of its ability to bind to and stimulate intestinal membrane-bound guanylate cyclase, generating cyclic GMP (cGMP). Previous work showed that a fucosylated oligosaccharide fraction of human milk was able to protect suckling mice from the secretory effects of STa, but the mechanism of the protection could not be determined. Oligosaccharide fractions from human milk were tested for their ability to block the biochemical effects of STa in T84 cells, a human colon carcinoma line responsive to the toxin. Total and fucosylated oligosaccharide fractions were found to inhibit STa-stimulated guanylate cyclase activity in T84 cell membranes and cGMP production in intact T84 cells by 60-80%. In addition, the total oligosaccharide fraction and the fucosylated oligosaccharide fraction inhibited 125I-STa binding significantly (17% and 27% inhibition, respectively). These findings demonstrate the protective activity of human milk oligosaccharides against STa in a human-derived cell line and show that the biochemical step blocked by oligosaccharides is STa-mediated stimulation of guanylate cyclase. This represents a novel mechanism by which human milk oligosaccharides protect against diarrhea.

Effects of a Soluble Guanylate Cyclase Stimulator Riociguat on Contractility of Isolated Pulmonary Artery and Hemodynamics of U46619-Induced Pulmonary Hypertension in Dogs

Soluble guanylate cyclase (sGC) stimulator riociguat is a relatively novel therapeutic agent for pulmonary hypertension (PH) in human medicine. Riociguat induces endothelium-independent pulmonary artery (PA) relaxation by directly activating the sGC-cyclic guanosine-3',5'-monophosphate (cGMP) pathway in muscle cells. Although riociguat may be effective in the treatment of dogs with refractory PH, basic studies on its clinical application in veterinary medicine are lacking. The present study aimed to explore the effects of riociguat on the contractility of an isolated canine PA and the hemodynamics of dogs with acute PH. In an isolated endothelium-denuded canine PA, the effects of riociguat on endothelin (ET)-1-induced contraction and cGMP levels were investigated using the Magnus method and ELISA, respectively. The effect of riociguat on the hemodynamics of the thromboxane A2 analog U46619-induced PH model dog was examined by invasive catheterization. Riociguat increased cGMP levels and reduced ET-1-induced contraction of the isolated PA. Riociguat inhibited the U46619-induced elevation of PA pressure and pulmonary vascular resistance and increased cardiac output, but it had no effect on basal systemic blood pressure. These results demonstrate for the first time that riociguat can inhibit the elevation of PA pressure through PA relaxation via an endothelium-independent increase in cGMP in dogs with PH.

Applicability of Vericiguat to Patients Hospitalized for Heart Failure in the United States

BackgroundIn January 2021, vericiguat, a soluble guanylate cyclase stimulator, was approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of cardiovascular death and heart failure (HF) hospitalization among patients with a recent worsening HF event based on the VICTORIA (VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. ObjectivesThis study sought to leverage a contemporary U.S. registry of patients hospitalized for heart failure (HF) to characterize patients who may be candidates for vericiguat based on FDA label and the VICTORIA trial eligibility criteria. MethodsThe authors studied patients hospitalized for HF with ejection fraction (EF) <45% across 525 sites in the GWTG-HF (Get With The Guidelines–Heart Failure) registry between January 2014 and December 2020. Approximate FDA label criteria (excluding estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, dialysis, or patients with heart transplantation or durable mechanical circulatory support) and eligibility criteria for the VICTORIA trial were applied to the GWTG-HF cohort. ResultsAmong 241,057 patients with EF <45% in the GWTG-HF registry, 221,730 (92%) could be candidates for vericiguat under the FDA label and 92,249 (38%) would have been eligible for the VICTORIA trial. The most frequent reasons for ineligibility for the FDA label were eGFR <15 mL/min/1.73 m2 (5.7%) and dialysis (1.6%). Although there were greater proportions of women and Black patients in the GWTG-HF registry, most clinical characteristics were qualitatively similar with patients enrolled in the VICTORIA trial. Among Medicare beneficiaries in the GWTG-HF registry eligible for vericiguat by either FDA label or VICTORIA trial criteria, 12-month postdischarge rates of mortality (36%-37%), HF hospitalization (33%-35%), all-cause hospitalization (64%-66%), and mean health care expenditure (U.S. $25,106-$25,428) were high. ConclusionsData from a large, contemporary U.S. registry of patients actively hospitalized for HF with EF <45% suggest that approximately 4 in 10 patients meet the criteria of the VICTORIA trial and that more than 9 in 10 patients are potential candidates for vericiguat based on the FDA label. Contemporary Medicare beneficiaries hospitalized for HF with EF <45% and eligible for vericiguat face high rates of postdischarge mortality and readmission and accrue substantial health care costs.

Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy.

Background: The chemotherapeutic doxorubicin (DOX) promotes severe skeletal muscle atrophy, which induces skeletal muscle weakness and fatigue. Soluble guanylate cyclase (sGC) contributes to a variety of pathophysiological processes, but whether it is involved in DOX-induced skeletal muscle atrophy is unclear. The present study aimed to stimulate sGC by vericiguat, a new oral sGC stimulator, to test its role in this process. Methods: Mice were randomly divided into four groups: control group, vericiguat group, DOX group, and DOX + vericiguat group. Exercise capacity was evaluated before the mice were sacrificed. Skeletal muscle atrophy was assessed by histopathological and molecular biological methods. Protein synthesis and degradation were monitored in mice and C2C12 cells. Results: In this study, a significant decrease in exercise capacity and cross-sectional area (CSA) of skeletal muscle fibers was found in mice following DOX treatment. Furthermore, DOX decreased sGC activity in mice and C2C12 cells, and a positive correlation was found between sGC activity and CSA of skeletal muscle fibers in skeletal muscle. DOX treatment also impaired protein synthesis, shown by puromycin detection, and activated ubiquitin-proteasome pathway. Following sGC stimulation, the CSA of muscle fibers was elevated, and exercise capacity was enhanced. Stimulation of sGC also increased protein synthesis and decreased ubiquitin-proteasome pathway. In terms of the underlying mechanisms, AKT/mTOR and FoxO1 pathways were impaired following DOX treatment, and stimulation of sGC restored the blunted pathways. Conclusion: These results unravel sGC stimulation can improve skeletal muscle atrophy and increase the exercise capacity of mice in response to DOX treatment by enhancing protein synthesis and inhibiting protein degradation. Stimulation of sGC may be a potential treatment of DOX-induced skeletal muscle dysfunction.

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy

BackgroundCirculating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. Methods and ResultsHigh-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14–1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. Conclusionshs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

Soluble guanylate cyclase stimulator riociguat in the palette of modern specific therapy for precapillary pulmonary hypertension: from the pathophysiological basis to the results of current research

Among the forms of precapillary pulmonary hypertension (PH) are pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) with a diagnostic triad of hemodynamic parameters: mean pulmonary artery pressure &gt; 25 mm Hg (&gt; 20 mm Hg according to the new version of European guidelines 2022), pulmonary artery wedge pressure ≥ 15 mm Hg; pulmonary vascular resistance &gt; 3 Wood units (&gt; 2 Wood units in the new version of European guidelines 2022) by right heart catheterization at rest. The leading factors in the pathogenesis of PAH are an endothelial dysfunction with an imbalance between vasodilating and vasoconstrictor substances, activation of endothelial/smooth muscle cell proliferation and the blood coagulation system, which lead to remodeling of the vessels of the pulmonary circulation. In CTEPH there is a morphological substrate as a chronic obstruction of large and medium branches of pulmonary arteries, as well as secondary changes in the microcirculatory bed of the lungs, and chronic/organized thrombi/emboli in the elastic type of pulmonary arteries are detected after three months of effective anticoagulant therapy.As a result of a significant progress in the study of the pathophysiological aspects of PAH in recent years, specific therapy has been introduced into clinical practice with an impact on key targets of the pathogenesis of the disease. In CTEPH pulmonary endarterectomy remains the treatment of choice for all operable patients. In case of inoperable and residual forms of CTEPH, if technically feasible, pulmonary artery balloon angioplasty is performed while taking PAH-specific drugs, in particular, the only officially approved stimulator of soluble guanylate cyclase (sGC) riociguat.The most important aspects of PAH-specific therapy of patients with PAH, inoperable and residual forms of CTEPH; the targets of therapy are indicated, promising approaches to therapy with a focus on the sGC stimulator riociguat, the possibilities of combination therapy and switching strategies are discussed in the article. The optimal safety and efficacy profile of riociguat, demonstrated in large international studies and routine clinical practice, allows the drug to be widely used in the treatment of patients with PAH and CTEPH. Switching from phosphodiesterase type 5 (PDE5) inhibitors to riociguat is safe and appropriate, which is emphasized in the Eurasian and Russian clinical guidelines, in 2022. the strategy of switching to riociguat is approved in case of failure of PDE5 inhibitors as part of combination therapy with endothelin receptor antagonists in the new version of the European document.The originality of riociguat due to the presence of a dual mechanism of action by direct stimulation of sGC and sensitization of the enzyme to endogenous NO, allows its use not only as a long-term monotherapy, but also as part of a combination therapy, with the implementation of a switching strategy in case of clinical failure of PDE5 inhibitors.

Expert Opinion on the Identification and Pharmacological Management of Worsening Heart Failure

Worsening heart failure (WHF) is a distinct under-diagnosed and under-treated condition, independent of location of care. Heart failure (HF) progression is punctuated by repeated WHF events, each resulting in reduced cardiac function. One-third of the patients with HF with reduced ejection fraction experience a decompensation event. These decompensation events often result in the emergency department visits and HF hospitalization. Despite its inclusion in recent guidelines, there is no precise definition of WHF or its various forms. It is worth noting that WHF signals a need for treatment optimization as per guideline-directed medical therapy and the addition of novel drugs like a stimulator of soluble guanylate cyclase that benefit this high-risk patient population. This practical document is based on the expert opinion of cardiologists, cardiothoracic surgeons, and physicians that discussed the definition, assessment, pharmacological management, and monitoring of WHF patients in a hospitalized setting. In addition, there is also a need for an expert opinion for the management of WHF in an outpatient setting.