Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Hydrogen sulfide regulates the redox state of soluble guanylate cyclase in CSE-/- mice corpus cavernosum microcirculation.

The corpus cavernosum (CC) is a highly vascularized tissue and represents an excellent example of microcirculation. Indeed, erectile dysfunction is considered an early index of cardiovascular disease. Hydrogen sulfide (H2S) at the vascular level is endogenously produced from L-cysteine mainly by the action of cystathionine-γ-lyase (CSE) and plays a role in CC vascular homeostasis. Here we have evaluated the involvement of the endogenous H2S in the regulation of the soluble guanylate cyclase (sCG) redox state. The lack of CSE-derived endogenous H2S, in CSE-/- mice, disrupted the eNOS/NO/sGC/PDE pathway. Indeed, the absence of CSE-derived endogenous H2S caused a significant reduction of the relaxant response to riociguat, an sGC redox-dependent stimulator. Conversely, the response to cinaciguat, an sGC redox-independent activator, was not modified. The relevance of the role played at the redox level of the endogenous H2S was confirmed by the findings that in CC harvested from CSE-/- mice there was a significant reduction of GCß1 expression coupled with a decrease in CYP5R3, a reductase involved in the regulation of the redox state of sGC. These molecular changes driven by the lack of endogenous H2S translate into a significant reduction in cGMP levels. The replenishment of the lack of H2S with an H2S donor rescued the relaxant response to riociguat in CC of CSE-/- mice. In conclusion, the endogenous CSE-derived H2S plays a physiological key role in the regulation of the redox state of sGC in CC microcirculation.

Soluble Guanylate Cyclase Activators and Stimulators in Patients with Heart Failure.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial.

AIMS: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. METHODS AND RESULTS: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. CONCLUSION: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm.

Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (n = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (n = 30), and patients (Group 2) in the chronic stage of CAS (n = 16). As expected, responses to SNP were impaired (p = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (p = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; p = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS.

Soluble Guanylyl Cyclase Activators-Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Impact of Innovative Treatment Using Biological Drugs for the Modulation of Diffuse Cutaneous Systemic Sclerosis: A Systematic Review.

Scleroderma or systemic sclerosis (SSc) is an autoimmune disease affecting the connective tissue, characterized by fibrosis of the skin and internal organs. There is currently no curative treatment available, so therapeutic action is aimed at a symptomatic treatment of the affected organs. The development of biotechnology has made it possible to implement certain biological drugs that could represent a window of opportunity to modulate the evolution and symptomatology of scleroderma with greater efficacy and less toxicity than conventional treatments. This study aimed to review the current evidence critically and systematically on the effects of biological drugs on the pulmonary function, skin disease, and health status of patients afflicted by diffuse cutaneous systemic sclerosis (dcSSc). Three electronic databases (Pubmed, Dialnet, and Cochrane Library Plus) were systematically searched until the cut-off date of October 2022. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included original articles in English and Spanish with a controlled trial design, comparing biological drug treatments (tocilizumab, belimumab, riociguat, abatacept, and romilkimab) with a control group. The methodological quality of the studies was assessed using the McMaster quantitative form and the PEDro scale. A total of 383 studies were identified, 6 of them met the established criteria and were included in the present systematic review. A total of 426 patients treated with tocilizumab, belimumab, riociguat, abatacept, and romilkimab were included. The results showed substantial non-significant (p < 0.05) improvement trends after treatment with the biological drugs included in this review for the modified Rodnan Scale Value, Forced Vital Capacity, and Carbon Monoxide Diffusion Test; however, no benefits were shown on the Health Assessment Questionnaire-Disability Index when compared to the control group. Biological drugs, therefore, maybe a new therapeutic strategy for dcSSc and could be recommended as an additional and/or adjunctive treatment that promotes anti-fibrotic activity. This review could further define the clinical rationale for the use of biologics in the treatment of dcSSc and could provide key details on the study protocol, design, and outcome reporting.

Targeting soluble guanylate cyclase with Riociguat has potency to alleviate testicular ischaemia reperfusion injury via regulating various cellular pathways.

Testicular ischaemia reperfusion (I/R) injury results with serious dysfunctions in testis. This study aims to explore effects of soluble guanylate cyclase (sGC) stimulator Riociguat on experimental testicular I/R injury in rats. Twenty-one male rats were divided into three groups (Control, IR and IRR). The control group was not exposed to any application. Bilateral testis from IR and IRR animals were rotated 720° in opposite directions for 3 h to induce experimental testicular ischaemia. Animals in IR and IRR groups were subjected to 3 h of reperfusion. Isotonic and Riociguat were administered to the animals 30 min prior reperfusion by oral gavage. At the end of experiment, animals were sacrificed and tissue samples were used for analyses. Riociguat treatment significantly decreased tissue malondialdehyde and Luminol levels compared to the IR group (p < 0.05). The pathological changes, pro-apoptotic proteins (Bax, Caspase 3, and Caspase 9) and apoptotic index in the IR group were down regulated in Riociguat treated animals (p < 0.05). Riociguat treatment was also significantly increased anti-apoptotic Bcl-2 expression, but alleviated tissue injury via modulating pro-inflammatory cytokine IL-1ß levels and significantly (p < 0.05) down-regulating NF-κB activity. Moreover, mTOR and ERK phosphorylation increased in IR group (p < 0.05), but Riociguat treatment reduced protein phosphorylation. Our experiment indicated that targeting sGC might support surgical interventions in testicular I/R injury by modulating oxidative stress, inflammation, and apoptotic protein expression levels, but more detailed studies are required to explore the protective activity of Riociguat and underlying mechanisms in testicular I/R injury.

Riociguat can ameliorate bronchopulmonary dysplasia in the SU5416 induced rat experimental model.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature neonates. Classical BPD is caused by hyperoxia and high-pressure mechanical ventilation, whereas BPD in recent era is caused by impaired pulmonary angiogenesis and alveolarization in extreme prematurity. Although sildenafil was reported to be effective in a hyperoxia-induced rat BPD model, several clinical trials could not demonstrate any significant improvement in the respiratory statuses of BPD infants. Riociguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate activity in a nitric oxide independent manner. However, a beneficial effect in BPD has not been established yet. METHODS AND RESULTS: We established BPD model in rats by injection of SU5416 on day 1 followed by maintenance under normoxia, which resulted in oversimplified alveoli, sparse pulmonary capillary vessels, severe pulmonary hypertension, and growth retardation, which mimicked the features observed in recent clinical management of BPD. We administered riociguat from day 10, when BPD rats exhibited growth retardation. Histological analyses demonstrated that riociguat treatment significantly but partially ameliorated lung alveolarization, vascularization, and pulmonary hypertension. However, the survival rate was not significantly improved by riociguat treatment. CONCLUSIONS: Riociguat could ameliorate pulmonary alveolarization, vascularization, and hypertension in the SU5416 induced BPD rat model, but could not improve the overall survival.

Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury.

Increased expression and activity of the Ca2+ channel transient receptor potential channel 6 (TRPC6) is associated with focal segmental glomerulosclerosis, but therapeutic strategies to target TRPC6 are currently lacking. Nitric oxide (NO) is crucial for normal glomerular function and plays a protective role in preventing glomerular diseases. We investigated if NO prevents podocyte injury by inhibiting injurious TRPC6-mediated signaling in a soluble guanylate cyclase (sGC)-dependent manner and studied the therapeutic potential of the sGC stimulator Riociguat. Experiments were performed using human glomerular endothelial cells and podocytes. Podocyte injury was induced by Adriamycin incubation for 24 h, with or without the NO-donor S-Nitroso-N-acetyl-DL-penicillamine (SNAP), the sGC stimulator Riociguat or the TRPC6 inhibitor Larixyl Acetate (LA). NO and Riociguat stimulated cGMP synthesis in podocytes, decreased Adriamycin-induced TRPC6 expression, inhibited the Adriamycin-induced TRPC6-mediated Ca2+ influx and reduced podocyte injury. The protective effects of Riociguat and NO were blocked when sGC activity was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or when TRPC6 activity was inhibited by LA. Our data demonstrate a glomerular (e)NOS-NO-sGC-cGMP-TRPC6 pathway that prevents podocyte injury, which can be translated to future clinical use by, e.g., repurposing the market-approved drug Riociguat.

Revisiting a Distinct Entity in Pulmonary Vascular Disease: Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Chronic thromboembolic pulmonary hypertension (CTEPH) is a specific type of pulmonary hypertension (PH) and the major component of Group 4 pulmonary hypertension (PH). It is caused by pulmonary vasculature obstruction that leads to a progressive increase in pulmonary vascular resistance and, ultimately, to failure of the right ventricle. Pulmonary thromboendarterectomy (PEA) is the only definitive therapy, so a timely diagnosis and early referral to a specialized PEA center to determine candidacy is prudent for a favorable outcome. Percutaneous balloon pulmonary angioplasty (BPA) has a potential role in patients unsuitable for PEA. Medical therapy with riociguat is the only PH-specific medical therapy currently approved for the treatment of inoperable or persistent CTEPH. This review article aims to revisit CTEPH succinctly with a review of prevailing literature.

[Optimization of specific therapy for pulmonary hypertension: the possibilities of riociguat].

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.

Riociguat ameliorates kidney injury and fibrosis in an animal model.

Chronic kidney disease (CKD) is one of the greatest health burdens with an increasing global prevalence. Renal fibrosis (RF) is the hallmark of all forms of CKD which shows a strong positive correlation with severity of the disease. However, there are no therapeutic options available for treatment of RF. In the present study, we used an animal model based on unilateral ureteral obstruction (UUO), for renal injury and fibrosis. The UUO animals were treated with soluble guanylyl cyclase (sGC) stimulator, riociguat (RIO) (1, 3 and 10 mg/kg) to investigate its possible renoprotective effects. Kidneys of animals treated with RIO were found to show less abnormalities as compared to UUO control. Further, the levels of proinflammatory cytokines were reduced in RIO treated group. Furthermore, administration of RIO reduced expression of collagen-1, TGF-ß, CTGF, α-SMA, vimentin along with transcription factors including Snail and Slug. The results of the present study provided strong evidence to support the antifibrotic activity of RIO.

Sensitive CE-MS method for monitoring of riociguat and desmethylriociguat levels in human serum.

Riociguat is novel antihypertensive drug for treatment of pulmonary hypertension. As such, it is still being tested in many clinical and pharmacokinetic trials. Existing methods that determine serum riociguat and desmethylriociguat (DMR) are based solely on liquid chromatography with mass spectrometry. Therefore, we present a novel capillary electrophoresis with mass spectrometry method (CE-MS) for their determination in human serum as alternative method for ongoing trials. Complete resolution of both analytes was achieved by means of pH optimization of ammonium formate background electrolytes that are fully compatible with ESI/MS detection. Simple liquid-liquid extraction was used as sample pretreatment. The calibration dependence of the method was linear (in the range of 10-1000 ng/mL), with adequate accuracy (90.1-114.9%) and precision (13.4%). LOD and LOQ were arbitrarily set at 10 ng/mL for both analytes. Clinical applicability was validated using serum samples from patients treated with riociguat in pharmacokinetic study and the results corresponded with reference HPLC-MS/MS values. Capillary electrophoresis proved to be sensitive and selective tool for the analysis of riociguat and DMR.

Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism.

BACKGROUND: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). METHODS: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. RESULTS: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. CONCLUSIONS: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.

Chronic Thromboembolic Pulmonary Hypertension-Management Strategies and Outcomes.

Chronic thromboembolic pulmonary hypertension (CTEPH) is rare but complex pathophysiological disease with hallmark features of chronic thrombotic mechanical obstruction, right ventricular dysfunction, and secondary pulmonary arteriopathy. It increasingly is being understood that chronic infection/inflammation, abnormal fibrinolysis, and cytokines play an important role in pathogenesis such that only a subset of patients with pulmonary embolism develop CTEPH. Diagnosis remains challenging given the lack of early clinical signs and overlap with other cardiopulmonary conditions. Pulmonary endarterectomy is the surgical procedure of choice with good postoperative survival and functional outcomes, especially when done at high-volume centers with a multidisciplinary approach. There has been a resurgence of balloon pulmonary angioplasty (BPA) as salvage therapy for inoperable CTEPH or in its newfound hybrid role for persistent postoperative pulmonary hypertension with excellent 1-year and 3-year survival. Use of riociguat has shown promising improvements in functional outcomes up to 2 years after initiation. Endothelin receptor antagonists serve a supplemental role postoperatively or in inoperable CTEPH. The role of drug therapy preoperatively or in tandem with BPA is currently under investigation.

Riociguat Improves Pulmonary Hemodynamics in Patients with Inoperable Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Few studies have investigated the effects of riociguat on pulmonary hemodynamics in Asian patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study, we evaluated the effects of riociguat on pulmonary hemodynamics in inoperable CTEPH patients. METHODS: We retrospectively collected the clinical data of 11 inoperable CTEPH patients. Pulmonary hemodynamic parameters of right heart catheterization, echocardiography, 6-minute walk distance and World Health Organization (WHO) functional class were assessed at baseline and after riociguat treatment. RESULTS: The median duration of riociguat treatment was 12 months, and all 11 patients tolerated riociguat 7.5 mg/day well after titration. With regards to pulmonary hemodynamic data, both mean pulmonary artery pressure and pulmonary vascular resistance significantly decreased from 41 ± 8 mmHg to 38 ± 9 mmHg (p = 0.045) and 787 ± 417 dyn·s·cm-5 to 478 ± 267 dyn·s·cm-5 (p = 0.007), respectively. With regards to clinical symptoms, WHO functional class significantly improved in nine of the 11 patients, and there was no change in the other two patients (p = 0.004). In addition, the median level of N-terminal pro-brain natriuretic peptide also significantly decreased from 281 (117-5943) pg/ml to 226 (48-1276) pg/ml (p = 0.021). CONCLUSIONS: Riociguat treatment improved both clinical symptoms and pulmonary hemodynamics in the inoperative CTEPH patients in this study.

[The achievements of the modern specific therapy of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: focus on the stimulator of soluble guanylate cyclase riociguat].

Currently, treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is focused on three signaling pathways: the NO pathway, the endothelin pathway, and the prostacyclin pathway. Riociguat is the only representative of stimulators of the soluble guanylate cyclase (sGC) class that is approved for the treatment of PAH and inoperable and persistent/recurrent CTEPH. The review presents data from clinical trials showing a positive effect of riociguat on the functional and hemodynamic profile of patients with PAH and CTEPH. In recent years there has been much discussion about the possibility of optimizing therapy by switching to drugs that affect a single pathogenesis target. Thus, sGC stimulants have obvious advantages over phosphodiesterase type 5 (PDE-5) inhibitors, including the ability of riociguat to exert pharmacological effects (due to a NO-independent mechanism of action) even in conditions of reduced NO production. Switching from PDE-5 to riociguat may be safe and appropriate, according to clinical trials presented in the review. In accordance with the guidelines for the diagnosis and treatment of pulmonary hypertension of the Eurasian Association of cardiologists from 2019, this strategy is approved when PDE5 therapy is ineffective in patients with PAH FC III (WHO).

[Possibility of complex medicamental and endovascular treatment of pulmonary hypertension in Takayasu arteritis with predominant pulmonary arteries' lesion].

Takayasu arteritis (TA) is a systemic vasculitis with predominatly lesions of aorta and its large branches. In some cases pulmonary arteries (PA) are involved in the pathological inflammatory process and lead to the formation of pulmonary hypertension and significantly worse the prognosis. Timely development of lesion of PA, appointment of adequate therapy and surgical treatment can prevent irreversible damage of blood vessels and improve the prognosis. Perioperative administration of interleukin-6 inhibitor inhibitor (tocilizumab) in at patients with indications for vascular surgery, including angioplasty PA, should be considered as a promising approach to control the inflammatory activity of TA, reduce the dose of glucocorticoids and the risk of postoperative complications. We present the clinical experience of significant improvement in the patients condition was achieved by using two-stage balloon angioplasty on the background of control of the disease activity with interleukin-6 tocilizumab intravenously and specific therapy with riociguat and iloprost.