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Right ventricular (RV) function is the main determinant of the outcome of patients with pulmonary hypertension (PH). RV dysfunction develops gradually and worsens progressively over the course of PH, resulting in RV failure and premature death. Currently, approved therapies for the treatment of left ventricular failure are not established for the RV. Furthermore, the direct effects of specific vasoactive drugs for treatment of pulmonary arterial hypertension (PAH, Group 1 of PH) on RV are not fully investigated. Pulmonary artery banding (PAB) allows to study the pathogenesis of RV failure solely, thereby testing potential therapies independently of pulmonary vascular changes. This review aims to discuss recent studies of the mechanisms of RV remodeling and RV-directed therapies based on the PAB model.

Background/Aims: Long-term high altitude residence leads to a sustained increase in pulmonary vascular resistance and elevation of pulmonary artery pressure due to chronic alveolar hypoxia. However...

Pulmonary hypertension (PH) is a devastating condition characterized by pulmonary vascular remodelling, leading to progressive increase in pulmonary artery pressure and subsequent right ventricular failure. Aldosterone and the mineralocorticoid receptor (MR), a nuclear transcription factor, are key drivers of cardiovascular disease and MR antagonists are well-established in heart failure. Now, a growing body of evidence points at a detrimental role of MR in PH. Pharmacological MR blockade attenuated PH and prevented RV failure in experimental models. Mouse models with cell selective MR deletion suggest that this effect is mediated by MR in endothelial cells. While the evidence from experimental studies appears convincing, the available clinical data on MR antagonist use in patients with PH is more controversial. Integrated analysis of clinical data together with MR-dependent molecular alterations may provide insights why some patients respond to MRA treatment while others do not. Potential ways to identify MRA ‘responders’ include the analysis of underlying PH causes, stage of disease, or sex, as well as new biomarkers.

Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.

This article reviews the scientific reasons that support the intriguing vision of pulmonary hypertension (PH) as a disease with a cancer-like nature and to understand whether this pointof view may have fruitful consequences for the overall management of PH. This review compares cancer and PH in view of Hanahan and Weinberg’s principles (i.e., hallmarks of cancer) with an emphasis on hyperproliferative, metabolic, and immune/inflammatory aspects of the disease.In addition, this review provides a perspective on the role of transcription factors and chromatin and epigenetic aberrations, besides genetics, as ‘‘common driving mechanisms’’ of PH hallmarks and the foreseeable use of transcription factor/epigenome targeting as multitarget approach against the hallmarks of PH. Thus, recognition of the widespread applicability and analogy of these concepts will increasingly affect the development of new means of PH treatment.

Pulmonary arterial hypertension is a severe respiratory disease characterized by pulmonary artery remodeling. RV dysfunction and dysregulated circulating metabolomics are associated with adverse outcomes in pulmonary arterial hypertension. We investigated effects of tadalafil and macitentan alone or in combination on the RV and plasma metabolomics in SuHx and PAB models. For SuHx model, rats were injected with SU5416 and exposed to hypoxia for three weeks and then were returned to normoxia and treated with either tadalafil (10 mg/kg in chow) or macitentan (10 mg/kg in chow) or their combination (both 10 mg/kg in chow) for two weeks. For PAB model, rats were subjected to either sham or PAB surgery for three weeks and treated with above-mentioned drugs from week 1 to week 3. Following terminal echocardiographic and hemodynamic measurements, tissue samples were collected for metabolomic, histological and gene expression analysis. Both SuHx and PAB rats developed RV remodeling/dysfunction with severe and mild plasma metabolomic alterations, respectively. In SuHx rats, tadalafil and macitentan alone or in combination improved RV remodeling/function with the effects of macitentan and combination therapy being superior to tadalafil. All therapies similarly attenuated SuHx-induced changes in plasma metabolomics. In PAB rats, only macitentan improved RV remodeling/function, while only tadalafil attenuated PAB-induced changes in plasma metabolomics.

Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.

International audience; In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of α-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-β1 from the extracellular matrix (ECM) stores. Liberation of active TGF-β1 from the ECM further enhances α-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.

Supplemental material, sj-pdf-1-pul-10.1177_2045894020947283 for Effects of macitentan and tadalafil monotherapy or their combination on the right ventricle and plasma metabolites in pulmonary hypertensive rats by Argen Mamazhakypov, Astrid Weiß, Sven Zukunft, Akylbek Sydykov, Baktybek Kojonazarov, Jochen Wilhelm, Christina Vroom, Aleksandar Petrovic, Djuro Kosanovic, Norbert Weissmann, Werner Seeger, Ingrid Fleming, Marc Iglarz, Friedrich Grimminger, Hossein A. Ghofrani, Soni S. Pullamsetti and Ralph T. Schermuly in Pulmonary Circulation

Background. Recent studies have reported that obstructive sleep apnea (OSA) patients present alterations in right ventricular (RV) structure and function. However, large randomized controlled trials evaluating the impact of OSA on the right ventricle are lacking. Methods. A comprehensive electronic database (PubMed, Web of Science, and Google Scholar) and reference search up to October 30, 2016, was performed. A systematic review and meta-analysis were performed to assess RV structure and function in OSA patients based on conventional echocardiography and tissue Doppler imaging. Results. Twenty-five studies with 1,503 OSA patients and 796 controls were included in this study. OSA patients exhibited an increase in RV internal diameter (weighted mean difference (WMD) (95% confidence intervals (CIs)) 2.49 (1.62 to 3.37); p=0.000) and RV wall thickness (WMD (95% CIs) 0.82 (0.51 to 1.13); p=0.000). Furthermore, OSA patients had a significantly elevated RV myocardial performance index (WMD (95% CI) 0.08 (0.06 to 0.10); p=0.000), decreased RV S’ (WMD (95% CI) −0.95 (−1.59 to −0.32); p=0.003), tricuspid annular plane systolic excursion (WMD (95% CI) −1.76 (−2.73 to −0.78); p=0.000), and RV fractional area change (WMD (95% CI) −3.16 (−5.60 to −0.73); p=0.011). Conclusion. OSA patients display RV dilatation, increased wall thickening, and altered RV function.

Pirfenidone (PFD) is an orally available synthetic drug which has been approved for the treatment of idiopathic pulmonary fibrosis. In addition to its anti-fibrotic properties, PFD also exerts anti-tumor effects in cancer models by inducing alterations in the tumor microenvironment. Here, we demonstrate that PFD reduces proliferation, 2D- and 3D-migration as well as colony formation of the non-small-cell lung carcinoma (NSCLC) cells. On a molecular level, we show that PFD on the one hand interacts with plasminogen activator inhibitor-1 (PAI-1; Kd of 46.2±11.3nM) and affects its inhibitory potency, but on the other hand it also increases PAI-1 expression; in both cases consequently leading to the reduction of urokinase (uPA) activity. Finally, we report that the effect of PFD on 2D-migration of NSCLC cells depends on PAI-1 expression and thus on the activity of the uPA system whereas the PFD-induced changes in cancer cell proliferation, 3D-migration and colony formation are PAI-1 independent. To conclude, a direct interference of PFD with the uPA-PAI-1 system may deregulate pericellular proteolytic activity and thereby influence the stability of the tumor blood vessels and the matrix architecture within tumor stroma.

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary artery remodelling leading to increased right ventricular pressure overload, which results in right heart failure and premature death. Inflammation plays a central role in the development of PAH, and the recruitment and function of immune cells are tightly regulated by chemotactic cytokines called chemokines. A number of studies have shown that the development and progression of PAH are associated with the dysregulated expression of several chemokines and chemokine receptors in the pulmonary vasculature. Moreover, some chemokines are differentially regulated in the pressure-overloaded right ventricle. Recent studies have tested the efficacy of pharmacological agents targeting several chemokines and chemokine receptors for their effects on the development of PAH, suggesting that these receptors could serve as useful therapeutic targets. In this review, we provide recent insights into the role of chemokines and chemokine receptors in PAH and RV remodelling and the opportunities and roadblocks in targeting them. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

Background Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO–sGC–cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction. Methods C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks. Results Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function. Conclusions Thus, modulation of the NO–sGC–cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.

Background and objectives: Pulmonary hypertension (PH) is characterized by the vasoconstriction and abnormally proliferative vascular cells. The available allopathic treatment options for PH are still not able to cure the disease. Alternative medicine is becoming popular and drawing the attention of the general public and scientific communities. The entomogenous fungus Yarsagumba (Cordyceps sinensis) and its biologically active ingredient cordycepin may represent the therapeutic option for this incurable disease, owing to their anti-inflammatory, vasodilatory and anti-oxidative effects. Methods: In this study, we investigated whether Yarsagumba extract and cordycepin possess anti-proliferative and vasorelaxant properties in the context of PH, using 5-bromo-2&rsquo, deoxyuridine assay and isolated mice lungs, respectively. Results: Our results revealed that Yarsagumba extract and its bioactive compound cordycepin significantly attenuated the proliferation of human pulmonary artery smooth muscle cells derived from donor and PH subjects. In isolated murine lungs, only Yarsagumba extract, but not cordycepin, resulted in vasodilatation, indicating the probable existence of other bioactive metabolites present in Yarsagumba that may be responsible for this outcome. Conclusion: Future comprehensive in vivo and in vitro research is crucially needed to discover the profound mechanistic insights with regard to this promising therapeutic potency of Yarsagumba extract and to provide further evidence as to whether it can be used as a strategy for the treatment of PH.

Pressure overload of the right ventricle (RV) in pulmonary arterial hypertension (PAH) leads to RV remodeling and failure, an important determinant of outcome in patients with PAH. Several G protein-coupled receptors (GPCRs) are differentially regulated in the RV myocardium, contributing to the pathogenesis of RV adverse remodeling and dysfunction. Many pharmacological agents that target GPCRs have been demonstrated to result in beneficial effects on left ventricular (LV) failure, such as beta-adrenergic receptor and angiotensin receptor antagonists. However, the role of such drugs on RV remodeling and performance is not known at this time. Moreover, many of these same receptors are also expressed in the pulmonary vasculature, which could result in complex effects in PAH. This manuscript reviews the role of GPCRs in the RV remodeling and dysfunction and discusses activating and blocking GPCR signaling to potentially attenuate remodeling while promoting improvements of RV function in PAH.

Pulmonary hypertension (PH) is a group of diseases characterized by increased pulmonary vascular resistance (PVR). Regardless of its cause, PH leads to right ventricular failure and premature death. Recent advances in the diagnosis and treatment of PH have prompted the elaboration of new guidelines for the diagnosis and treatment of PH. This paper provides a brief overview of major achievements in diagnostic and treatment approaches in patients PH.Легочная гипертония (ЛГ) - группа заболеваний, для которых характерно повышение легочного сосудистого сопротивления (ЛСС). Независимо от причины ЛГ приводит к развитию правожелудочковой сердечной недостаточности и преждевременной смерти. За последние годы достигнут значительный прогресс в диагностике и лечении больных с ЛГ, послуживший основой нового клинического руководства по диагностике и лечению ЛГ. В данной статье предлагается краткий обзор основных достижений в диагностических и терапевтических подходах у больных с ЛГ.

Right ventricular (RV) remodeling represents a complex set of functional and structural adaptations in response to chronic pressure or volume overload due to various inborn defects or acquired diseases and is an important determinant of patient outcome. However, the underlying molecular mechanisms remain elusive. We investigated the time course of structural and functional changes in the RV in the murine model of pressure overload‐induced RV hypertrophy in C57Bl/6J mice. Using magnetic resonance imaging, we assessed the changes of RV structure and function at different time points for a period of 21 days. Pressure overload led to significant dilatation, cellular and chamber hypertrophy, myocardial fibrosis, and functional impairment of the RV. Progressive remodeling of the RV after pulmonary artery banding (PAB) in mice was associated with upregulation of myocardial gene markers of hypertrophy and fibrosis. Furthermore, remodeling of the RV was associated with accumulation and activation of mast cells in the RV tissue of PAB mice. Our data suggest possible involvement of mast cells in the RV remodeling process in response to pressure overload. Mast cells may thus represent an interesting target for the development of new therapeutic approaches directed specifically at the RV.

High altitude pulmonary edema (HAPE) is a potentially life-threatening form of noncardiogenic pulmonary edema that may develop in otherwise healthy individuals upon ascent to high altitude. A constitutional susceptibility has been noted in some individuals, whereas others appear not to be susceptible at all. In our report, we present a case of HAPE triggered by concurrent respiratory tract infection and strenuous exercise in a mining worker with an abnormal rise in pulmonary artery pressure in response to acute hypoxia, without a prior history of HAPE during almost a year of commuting between high altitude and lowland areas.