bay-63-2521 and Heart-Failure

Heart failure is associated with an impaired NO-soluble guanylyl cyclase (sGC)-cGMP pathway and its augmentation is thought to be beneficial for its therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat prevents pathological cardiac remodelling and heart failure in response to chronic pressure overload.. Transverse aortic constriction or sham surgery was performed in C57BL/6N mice. After 3 weeks of transverse aortic constriction when heart failure was established, animals receive either riociguat or its vehicle for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LVs) was analysed by RNA sequencing. Cell culture experiments were used for mechanistically studies.. Transverse aortic constriction resulted in a continuous decrease of LV ejection fraction and an increase in LV mass until week 3. Five weeks of riociguat treatment resulted in an improved LV ejection fraction and a decrease in the ratio of left ventricular mass to total body weight (LVM/BW), myocardial fibrosis and myocyte cross-sectional area. RNA sequencing revealed that riociguat reduced the expression of myocardial stress and remodelling genes (e.g. Nppa, Nppb, Myh7 and collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and heart failure. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts.. Stimulation of the sGC reverses transverse aortic constriction-induced heart failure and remodelling, which is associated with improved myocardial gene expression.. This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

Topics: Animals; Cyclic GMP; Heart Failure; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase; Ventricular Remodeling

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic PH leading to right heart failure and death. Lung ventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In the case of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm and define the pulmonary vascular involvement and prior to making a treatment decision. PH is confirmed with right heart catheterisation, which is also necessary for treatment determination. In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. For technically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based on the CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced with this challenging but potentially effective and complementary intervention.

Topics: Angiography; Angioplasty, Balloon; Anticoagulants; Cardiac Catheterization; Chronic Disease; Endarterectomy; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

Topics: Adult; Aged; Angioplasty, Balloon; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Molecular Targeted Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Walk Test

During the last 20 years, the prognosis for heart failure (HF) with reduced ejection fraction has steadily improved due to advances in drug treatment and the consistent implementation of guideline-recommended evidence-based drug therapy. Nevertheless, the morbidity and mortality rates of patients with HF can still be improved. The prevalence of HF is high and continues to increase steadily. Thus, timely and efficient drug treatment plays a central role in improving the quality of life and prognosis for patients with HF. Current therapeutic concepts combine inhibition of the renin-angiotensin-aldosterone system with blockage of the sympathetic system. New therapeutic approaches such as selective heart rate reduction, attenuation of the degradation of natriuretic peptides by neutral endopeptidase inhibition and treatment of comorbidities (e.g. iron deficiency, diabetes mellitus, hyperkalaemia) have led to a further improvement in the survival, time-out-of hospital and quality of life of affected patients. The goal of this article was to give an overview of the current standard drug therapy for HF and the value of new therapeutic approaches implemented in recent years.

Topics: Adrenergic beta-Antagonists; Algorithms; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzhydryl Compounds; Cardiac Glycosides; Cardiotonic Agents; Diuretics; Enzyme Activators; Glucosides; Heart Failure; Humans; Hyperkalemia; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Iron; Ivabradine; Mineralocorticoid Receptor Antagonists; Neprilysin; Practice Guidelines as Topic; Pyrazoles; Pyrimidines; Renin; Renin-Angiotensin System; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Urea

Several randomized controlled trials (RCTs) have been investigated the benefits of soluble guanylate cyclase (sGC) stimulators in the treatment of heart failure, but a comprehensive evaluation is lacking. We performed a meta-analysis to evaluate the efficacy and safety of oral sGC stimulators (vericiguat and riociguat) in patients with heart failure.. Studies were searched and screened in PubMed, Embase, and Cochrane Library. Eligible RCTs were included that reported mortality, the change of EuroQol Group 5-Dmensional Self-report Questionnaire (EQ-5D) US index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), or serious adverse events (SAEs). Relative risk or weight mean difference (WMD) was estimated using fixed effect model or random effect model. Analysis of sensitivity and publication bias was conducted.. Five trials with a total of 1200 patients were included. sGC stimulators had no impact on the mortality (1.25; 95% confidence interval 0.50-3.11) and significantly improved EQ-5D US index (0.04; 95% confidence interval 0.020-0.05). Furthermore, in comparison with control group, NT-proBNP was statistically decreased in riociguat group (-0.78; 95% confidence interval -1.01 to -0.47), but not in vericiguat group (0.04, 95% confidence interval -0.18 to 0.25). There were not obverse differences in SAEs between sGC stimulators and control groups (0.90; 95% confidence interval 0.72-1.12).. Our meta-analysis suggests that sGC stimulators could improve the quality of life in patients with heart failure with good tolerance and safety, but their long-term benefits need to be observed in the future. sGC stimulators are likely to be promising add-on strategies for the treatment of heart failure.

Topics: Adult; Aged; Enzyme Activators; Female; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pyrazoles; Pyrimidines; Quality of Life; Soluble Guanylyl Cyclase

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Topics: Benzoates; Cyclic GMP; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Nitric Oxide; Pyrazoles; Pyrimidines; Signal Transduction; Soluble Guanylyl Cyclase; Stroke Volume

This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3', 5'-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)-independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.

Topics: Benzoates; Cardiovascular Agents; Guanylate Cyclase; Heart Failure; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Signal Transduction

Development and progression of heart failure involve endothelial and myocardial dysfunction as well as a dysregulation of the NO-sGC-cGMP signalling pathway. Recently, we reported that the sGC stimulator riociguat has beneficial effects on cardiac remodelling and progression of heart failure in response to chronic pressure overload. Here, we examined if these beneficial effects of riociguat were also reflected in alterations of the myocardial proteome and microRNA profiles.. Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham-operated mice served as controls. TAC and sham animals were randomised and treated with either riociguat or vehicle for 5 weeks, starting 3 weeks after surgery, when cardiac hypertrophy was established. Afterwards, we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LVs).. TAC-induced changes of the LV proteome were significantly reduced by treatment with riociguat. Bioinformatics analyses revealed that riociguat improved TAC-induced cardiovascular disease-related pathways, metabolism and energy production, for example, reversed alterations in the levels of myosin heavy chain 7, cardiac phospholamban and ankyrin repeat domain-containing protein 1. Riociguat also attenuated TAC-induced changes of microRNA levels in the LV.. The sGC stimulator riociguat exerted beneficial effects on cardiac structure and function during pressure overload, which was accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of riociguat as a novel therapeutic agent for heart failure.

Topics: Animals; Aortic Valve Stenosis; Disease Models, Animal; Heart Failure; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Proteome; Pyrazoles; Pyrimidines; Ventricular Remodeling

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Stroke Volume

The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.

Topics: Administration, Intravenous; Administration, Oral; Animals; Blood Pressure; Chemistry Techniques, Synthetic; Dogs; Heart Failure; Hepatocytes; Heterocyclic Compounds, 2-Ring; Humans; Male; NG-Nitroarginine Methyl Ester; Pyrimidines; Rats, Transgenic; Rats, Wistar; Soluble Guanylyl Cyclase; Structure-Activity Relationship

New pharmacological approaches are introduced for the treatment of chronic right heart failure which aim at reduced mortality. Riociguat is a new drug for the treatment of chronic thrombembolic pulmonary hypertension. Transcatheter valve interventions are established for treatment of pulmonary valve diseases and introduced as promising upcoming therapeutic options for tricuspid regurgitation. The management of acute right heart failure is supported by the miniaturization of mechanical circulatory support systems with percutaneous cannulation applicable in terms of "Bridge to Recovery" and "Bridge to Decision" concepts and effective long-term support, respectively.

Topics: Cardiovascular Agents; Heart Failure; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Pyrazoles; Pyrimidines

Stimulation of the nitric oxide (NO)--soluble guanylate (sGC)--protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduces infarct size but also whether it protects against the development of post-MI heart failure.. Mice were subjected to 30 min ischaemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and (18)F-FDG-positron emission tomography (PET) were performed to determine infarct size. In the riociguat-treated mice, the resulting infarct size was smaller (8.5 ± 2.5% of total LV mass vs. 21.8% ± 1.7%. in controls, p = 0.005) and LV systolic function analysed by MRI was better preserved (60.1% ± 3.4% of preischaemic vs. 44.2% ± 3.1% in controls, p = 0.005). After 28 days, LV systolic function by echocardiography treated group was still better preserved (63.5% ± 3.2% vs. 48.2% ± 2.2% in control, p = 0.004).. Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size and better long-term preservation of LV systolic function. These findings suggest that sGC stimulation during reperfusion therapy may be a powerful therapeutic treatment strategy for preventing post-MI heart failure.

Topics: Animals; Biomarkers; Echocardiography; Guanylate Cyclase; Heart Failure; Hemodynamics; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Positron-Emission Tomography; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase