Right ventricular failure in pulmonary hypertension: recent insights from experimental models.

Right ventricular (RV) function is a critical determinant of the prognosis of patients with pulmonary hypertension (PH). Upon establishment of PH, RV dysfunction develops, leading to a gradual worsening of the condition over time, culminating in RV failure and premature mortality. Despite this understanding, the underlying mechanisms of RV failure remain obscure. As a result, there are currently no approved therapies specifically targeting the right ventricle. One contributing factor to the lack of RV-directed therapies is the complexity of the pathogenesis of RV failure as observed in animal models and clinical studies. In recent years, various research groups have begun utilizing multiple models, including both afterload-dependent and afterload-independent models, to investigate specific targets and pharmacological agents in RV failure. In this review, we examine various animal models of RV failure and the recent advancements made utilizing these models to study the mechanisms of RV failure and the potential efficacy of therapeutic interventions, with the ultimate goal of translating these findings into clinical practice to enhance the management of individuals with PH.

Clinical and Molecular Implications of Osteopontin in Heart Failure.

The matricellular protein osteopontin modulates cell-matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment.

Genetic Deficiency and Pharmacological Stabilization of Mast Cells Ameliorate Pressure Overload-Induced Maladaptive Right Ventricular Remodeling in Mice.

Although the response of the right ventricle (RV) to the increased afterload is an important determinant of the patient outcome, very little is known about the underlying mechanisms. Mast cells have been implicated in the pathogenesis of left ventricular maladaptive remodeling and failure. However, the role of mast cells in RV remodeling remains unexplored. We subjected mast cell-deficient WBB6F1-KitW/W-v (KitW/KitW-v) mice and their mast cell-sufficient littermate controls (MC+/+) to pulmonary artery banding (PAB). PAB led to RV dilatation, extensive myocardial fibrosis, and RV dysfunction in MC+/+ mice. In PAB KitW/KitW-v mice, RV remodeling was characterized by minimal RV chamber dilatation and preserved RV function. We further administered to C57Bl/6J mice either placebo or cromolyn treatment starting from day 1 or 7 days after PAB surgery to test whether mast cells stabilizing drugs can prevent or reverse maladaptive RV remodeling. Both preventive and therapeutic cromolyn applications significantly attenuated RV dilatation and improved RV function. Our study establishes a previously undescribed role of mast cells in pressure overload-induced adverse RV remodeling. Mast cells may thus represent an interesting target for the development of a new therapeutic approach directed specifically at the heart.

Yarsagumba is a Promising Therapeutic Option for Treatment of Pulmonary Hypertension due to the Potent Anti-Proliferative and Vasorelaxant Properties.

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'-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.

High Altitude Pulmonary Edema in a Mining Worker With an Abnormal Rise in Pulmonary Artery Pressure in Response to Acute Hypoxia Without Prior History of High Altitude Pulmonary Edema.

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.

Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle.

In response to various stressors, cardiac chambers undergo structural remodeling. Long-term exposure of the right ventricle (RV) to pressure or volume overload leads to its maladaptive remodeling, associated with RV failure and increased mortality. While left ventricular adverse remodeling is well understood and therapeutic options are available or emerging, RV remodeling remains underexplored, and no specific therapies are currently available. Accumulating evidence implicates the role of mast cells in RV remodeling. Mast cells produce and release numerous inflammatory mediators, growth factors and proteases that can adversely affect cardiac cells, thus contributing to cardiac remodeling. Recent experimental findings suggest that mast cells might represent a potential therapeutic target. This review examines the role of mast cells in cardiac remodeling, with a specific focus on RV remodeling, and explores the potential efficacy of therapeutic interventions targeting mast cells to mitigate adverse RV remodeling.

Atlas of cardiac endothelial cell enhancer elements linking the mineralocorticoid receptor to pathological gene expression.

Endothelial cells play crucial roles in physiology and are increasingly recognized as therapeutic targets in cardiovascular disease. Here, we analyzed the regulatory landscape of cardiac endothelial cells by assessing chromatin accessibility, histone modifications, and 3D chromatin organization and confirmed the functional relevance of enhancer-promoter interactions by CRISPRi-mediated enhancer silencing. We used this dataset to explore mechanisms of transcriptional regulation in cardiovascular disease and compared six different experimental models of heart failure, hypertension, or diabetes. Enhancers that regulate gene expression in diseased endothelial cells were enriched with binding sites for a distinct set of transcription factors, including the mineralocorticoid receptor (MR), a known drug target in heart failure and hypertension. For proof of concept, we applied endothelial cell-specific MR deletion in mice to confirm MR-dependent gene expression and predicted direct MR target genes. Overall, we have compiled here a comprehensive atlas of cardiac endothelial cell enhancer elements that provides insight into the role of transcription factors in cardiovascular disease.

Divergent and Compensatory Effects of BMP2 and BMP4 on the VSMC Phenotype and BMP4's Role in Thoracic Aortic Aneurysm Development.

Vascular smooth muscle cells (VSMCs) play a key role in aortic aneurysm formation. Bone morphogenetic proteins (BMPs) have been implicated as important regulators of VSMC phenotype, and dysregulation of the BMP pathway has been shown to be associated with vascular diseases. The aim of this study was to investigate for the first time the effects of BMP-4 on the VSMC phenotype and to understand its role in the development of thoracic aortic aneurysms (TAAs). Using the angiotensin II (AngII) osmotic pump model in mice, aortas from mice with VSMC-specific BMP-4 deficiency showed changes similar to AngII-infused aortas, characterised by a loss of contractile markers, increased fibrosis, and activation of matrix metalloproteinase 9. When BMP-4 deficiency was combined with AngII infusion, there was a significantly higher rate of apoptosis and aortic dilatation. In vitro, VSMCs with mRNA silencing of BMP-4 displayed a dedifferentiated phenotype with activated canonical BMP signalling. In contrast, BMP-2-deficient VSMCs exhibited the opposite phenotype. The compensatory regulation between BMP-2 and BMP-4, with BMP-4 promoting the contractile phenotype, appeared to be independent of the canonical signalling pathway. Taken together, these results demonstrate the impact of VSMC-specific BMP-4 deficiency on TAA development.

Therapeutic targeting of mineralocorticoid receptors in pulmonary hypertension: Insights from basic research.

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling and associated with adverse outcomes. In patients with PH, plasma aldosterone levels are elevated, suggesting that aldosterone and its receptor, the mineralocorticoid receptor (MR), play an important role in the pathophysiology of PH. The MR plays a crucial role in adverse cardiac remodeling in left heart failure. A series of experimental studies from the past few years indicate that MR activation promotes adverse cellular processes that lead to pulmonary vascular remodeling, including endothelial cell apoptosis, smooth muscle cell (SMC) proliferation, pulmonary vascular fibrosis, and inflammation. Accordingly, in vivo studies have demonstrated that pharmacological inhibition or cell-specific deletion of the MR can prevent disease progression and partially reverse established PH phenotypes. In this review, we summarize recent advances in MR signaling in pulmonary vascular remodeling based on preclinical research and discuss the potential, but also the challenges, in bringing MR antagonists (MRAs) into clinical application.

Surgical protocol for pulmonary artery banding in mice to generate a model of pressure-overload-induced right ventricular failure.

Right ventricular failure (RVF) is the leading cause of death in patients with pulmonary hypertension. Here, we present a protocol for pulmonary artery banding in mice to generate a model of pressure-overload-induced RVF. We describe steps for anesthesia of mice, endotracheal intubation, and pulmonary artery banding surgery. We then detail procedures for phenotyping and analysis. Our approach does not involve complete blockage of the pulmonary flow during clip placement and is, therefore, associated with low intraoperative mortality. For complete details on the use and execution of this protocol, please refer to Veith et al. (2020).1.

Osteopontin in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a pathological condition with multifactorial etiology, which is characterized by elevated pulmonary arterial pressure and pulmonary vascular remodeling. The underlying pathogenetic mechanisms remain poorly understood. Accumulating clinical evidence suggests that circulating osteopontin may serve as a biomarker of PH progression, severity, and prognosis, as well as an indicator of maladaptive right ventricular remodeling and dysfunction. Moreover, preclinical studies in rodent models have implicated osteopontin in PH pathogenesis. Osteopontin modulates a plethora of cellular processes within the pulmonary vasculature, including cell proliferation, migration, apoptosis, extracellular matrix synthesis, and inflammation via binding to various receptors such as integrins and CD44. In this article, we provide a comprehensive overview of the current understanding of osteopontin regulation and its impact on pulmonary vascular remodeling, as well as consider research issues required for the development of therapeutics targeting osteopontin as a potential strategy for the management of PH.

Mineralocorticoid receptors in pulmonary hypertension and right heart failure: From molecular biology to therapeutic targeting.

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.

Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season.

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.

The role of chemokines and chemokine receptors in pulmonary arterial hypertension.

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.

Right Ventricular Response to Acute Hypoxia Exposure: A Systematic Review.

Background: Acute hypoxia exposure is associated with an elevation of pulmonary artery pressure (PAP), resulting in an increased hemodynamic load on the right ventricle (RV). In addition, hypoxia may exert direct effects on the RV. However, the RV responses to such challenges are not fully characterized. The aim of this systematic review was to describe the effects of acute hypoxia on the RV in healthy lowland adults. Methods: We systematically reviewed PubMed and Web of Science and article references from 2005 until May 2021 for prospective studies evaluating echocardiographic RV function and morphology in healthy lowland adults at sea level and upon exposure to simulated altitude or high-altitude. Results: We included 37 studies in this systematic review, 12 of which used simulated altitude and 25 were conducted in high-altitude field conditions. Eligible studies reported at least one of the RV variables, which were all based on transthoracic echocardiography assessing RV systolic and diastolic function and RV morphology. The design of these studies significantly differed in terms of mode of ascent to high-altitude, altitude level, duration of high-altitude stay, and timing of measurements. In the majority of the studies, echocardiographic examinations were performed within the first 10 days of high-altitude induction. Studies also differed widely by selectively reporting only a part of multiple RV parameters. Despite consistent increase in PAP documented in all studies, reports on the changes of RV function and morphology greatly differed between studies. Conclusion: This systematic review revealed that the study reports on the effects of acute hypoxia on the RV are controversial and inconclusive. This may be the result of significantly different study designs, non-compliance with international guidelines on RV function assessment and limited statistical power due to small sample sizes. Moreover, the potential impact of other factors such as gender, age, ethnicity, physical activity, mode of ascent and environmental factors such as temperature and humidity on RV responses to hypoxia remained unexplored. Thus, this comprehensive overview will promote reproducible research with improved study designs and methods for the future large-scale prospective studies, which eventually may provide important insights into the RV response to acute hypoxia exposure.

Novel Therapeutic Targets for the Treatment of Right Ventricular Remodeling: Insights from the Pulmonary Artery Banding Model.

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.

Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.

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.

Hypoxia-inducible factor signaling in pulmonary hypertension.

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.

Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system.

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.