Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary ...vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.
Thyroid disease is common in patients with pulmonary hypertension (PH), but its effect on long-term survival remains unknown. We examined the prognostic significance of thyroid hormone levels of free ...triiodothyronine (fT3) and free thyroxine and thyroid-stimulating hormone (TSH), and thyroid hormone replacement (THR) therapy in PH.
We conducted a retrospective analysis of 1,756 patients enrolled in the Giessen PH Registry in 1999 to 2013 with baseline thyroid function data; of these, 355, 533, 498, and 370 had pulmonary arterial hypertension (PAH); including 192 with idiopathic PAH (iPAH), PH due to left heart disease, PH due to lung diseases, and chronic thromboembolic PH (CTEPH), respectively. Thyroid function parameters associated with mortality were identified using Cox regression and Kaplan-Meier analyses.
Transplant-free survival at 1, 3, and 5 years was 86.7%, 65.6%, and 53.0%, respectively. Absence of THR therapy was an independent predictor of death in iPAH (multivariate hazard ratio HR, 2.50; 95% confidence interval CI, 1.06-5.75). In patients without THR therapy, TSH levels in the lowest and highest quartiles (compared with the middle 2 quartiles) independently predicted death in iPAH (HR, 1.98; 95% CI, 1.07-3.67), whereas reduced fT3 levels were independently associated with increased death in PAH (HR, 8.30; 95% CI, 2.50-25.00) and CTEPH (HR, 1.79; 95% CI, 1.14-4.20).
Thyroid hormone levels and THR therapy are prognostic factors in iPAH, PAH, and CTEPH. Prospective studies are warranted to verify the prognostic significance of thyroid function and the effect of THR therapy in PH.
Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary ...arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inflammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pulmonary hypertension (PH) is a severe, progressive disease. Although 5 PH subgroups are recognized, reports on survival have focused mainly on pulmonary arterial hypertension (PAH).
Long-term ...transplant-free survival and its determinants were investigated in patients with PH (diagnosed by right heart catheterization) within a prospective registry at a single referral center in Giessen, Germany.
In total, 2,067 patients were enrolled (PAH, 685 patients 33.1%; pulmonary venous hypertension, 307 patients 14.9%; PH due to lung diseases (LD-PH), 546 patients 26.4%; mainly interstitial lung disease and chronic obstructive pulmonary disease; chronic thromboembolic PH, 459 patients 22.2%; PH owing to miscellaneous/unknown causes, 70 patients 3.4%). Median follow-up was 37 months. Differences in transplant-free survival between etiologic groups were highly significant (p < 0.001), with 1-, 3- and 5-year survival rates of 88.2%, 72.2% and 59.4%, respectively, for those with PAH compared with 79.5%, 52.7% and 38.1%, respectively, for patients with LD-PH. Patients’ age, gender and 6-minute walk distance (6MWD), but not New York Heart Association (NYHA) functional class, associated significantly with survival across all PH subtypes in multivariate Cox regression analyses.
This is the largest single-center PH cohort described so far. Some parameters used in clinical practice do not independently predict survival. Age, gender and 6MWD outperformed NYHA functional class in predicting survival across all etiologic groups.
Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary vascular ...remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef ), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins ...that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification.
In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint.
20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77–0·89; p<0·0001) to 0·91 (for panel and REVEAL 0·87–0·96; p<0·0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0·0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4·4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation.
A combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies.
National Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, Inserm, Université Paris-Sud, and Agence Nationale de la Recherche.
The heterozygous loss of function mutations in the Type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlies the majority of ...familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH, and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effects of currently used therapies on the TGF-β pathway remain unknown. Prostacyclin analogs comprise the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analog, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells (PASMCs) harboring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. Our study demonstrates that this agent inhibits TGF-β1-induced SMAD-dependent and SMAD-independent signaling via a protein kinase A-dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38 mitogen-activated protein kinase proteins. Finally, in a monocrotaline-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil, a stable prostacyclin analog, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogs inhibit dysregulated TGF-β signaling in vitro and in vivo, and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.
Abstract Direct vasodilator delivery to the airways enables a selective therapy of pulmonary hypertension (PH). However, short-term effects of the applied medication require multiple daily ...inhalations. Controlled release formulations (polymeric nanomedicines) offer the potential of prolonging drug effects within the respiratory tract, thereby reducing the number of necessary inhalations. In the model of U46619-elicited PH, sildenafil and two sildenafil-loaded polymeric submicron particle formulations were evaluated for their pharmacodynamic and pharmacokinetic characteristics and acute tolerability. Lung-delivered sildenafil caused a selective dose-dependent decline of the pulmonary arterial pressure and vascular resistance. Compared to the transient pharmacodynamic effect observed for sildenafil, the same dose of nanoencapsulated sildenafil resulted in prolongation, but not augmentation, of the pulmonary vasodilatation. An extended pharmacokinetic profile was observed for nanoencapsulated sildenafil, and nanomedicines revealed no acute toxicity. The amplification of pulmonary vasodilatory response caused by nanoencapsulation of sildenafil offers an intriguing approach to ameliorate the therapy of PH. From the Clinical Editor Pulmonary hypertension usually results in right heart failure long term. Current medical therapy includes the use of potent vasodilators such as sildenafil. In this article, the authors investigated the use of nanoencapsulated formulation for sustained delivery via inhalation route. An extended pharmacokinetic profile was seen for this nanoformulation with little side effects. It is hoped that clinical application of this would come to fruition soon.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Excessive release of nitric oxide from inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified ...imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible isoform. In the present study, we tested the in vivo potency of BYK191023 2-2-(4-methoxy-pyridin-2-yl)-ethyl-3H-imidazo-4,5-bpyridine, a selected member of this inhibitor class, in three different rat models of lipopolysaccharide-induced systemic inflammation. Delayed administration of BYK191023 dose-dependently suppressed the lipopolysaccharide-induced increase in plasma nitrate/nitrite (NO(x)) levels with an ED(50) of 14.9 micromol/kg/h. In a model of systemic hypotension following high-dose lipopolysaccharide challenge, curative administration of BYK191023 at a dose that inhibited 83% of the NO(x) increase completely prevented the gradual decrease in mean arterial blood pressure observed in vehicle-treated control animals. The vasopressor effect was specific for endotoxemic animals since BYK191023 did not affect blood pressure in saline-challenged controls. In addition, in a model of lipopolysaccharide-induced vascular hyporesponsiveness, BYK191023 infusion partially restored normal blood pressure responses to norepinephrine and sodium nitroprusside via an l-arginine competitive mechanism. Taken together, BYK191023 is a member of a novel class of highly isoform-selective iNOS inhibitors with promising in vivo activity suitable for mechanistic studies on the role of selective iNOS inhibition as well as clinical development.
The heterozygous loss of function mutations in the Type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-beta) receptor family, underlies the majority ...of familial cases of pulmonary arterial hypertension (PAH). The TGF-beta1 pathway is activated in PAH, and inhibitors of TGF-beta1 signaling prevent the development and progression of PAH in experimental models. However, the effects of currently used therapies on the TGF-beta pathway remain unknown. Prostacyclin analogs comprise the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-beta1 pathway. Beraprost sodium (BPS), a prostacyclin analog, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells (PASMCs) harboring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-beta1 stimulation. Our study demonstrates that this agent inhibits TGF-beta1-induced SMAD-dependent and SMAD-independent signaling via a protein kinase A-dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38 mitogen-activated protein kinase proteins. Finally, in a monocrotaline-induced rat model of PAH, which is associated with increased TGF-beta signaling, this study confirms that treprostinil, a stable prostacyclin analog, inhibits the TGF-beta pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogs inhibit dysregulated TGF-beta signaling in vitro and in vivo, and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.
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