Showing papers in "Pulmonary circulation in 2018"
TL;DR: The present review will provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development as one of the major topics included in the 2017 Grover Conference Series.
Abstract: Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.
97 citations
TL;DR: The evidence linking endothelial injury to COPD, and the pathways underlying endothelial Injury and the “vascular COPD phenotype” are reviewed, including direct toxic effects of cigarette smoke on endothelial cells are reviewed.
Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by chronic expiratory airflow obstruction that is not fully reversible. COPD patients develop varying degrees of emphysema, small and large airway disease, and various co-morbidities. It has not been clear whether these co-morbidities share common underlying pathogenic processes with the pulmonary lesions. Early research into the pathogenesis of COPD focused on the contributions of injury to the extracellular matrix and pulmonary epithelial cells. More recently, cigarette smoke-induced endothelial dysfunction/injury have been linked to the pulmonary lesions in COPD (especially emphysema) and systemic co-morbidities including atherosclerosis, pulmonary hypertension, and chronic renal injury. Herein, we review the evidence linking endothelial injury to COPD, and the pathways underlying endothelial injury and the "vascular COPD phenotype" including: (1) direct toxic effects of cigarette smoke on endothelial cells; (2) generation of auto-antibodies directed against endothelial cells; (3) vascular inflammation; (4) increased oxidative stress levels in vessels inducing increases in lipid peroxidation and increased activation of the receptor for advanced glycation end-products (RAGE); (5) reduced activation of the anti-oxidant pathways in endothelial cells; (6) increased endothelial cell release of mediators with vasoconstrictor, pro-inflammatory, and remodeling activities (endothelin-1) and reduced endothelial cell expression of mediators that promote vasodilation and homeostasis of endothelial cells (nitric oxide synthase and prostacyclin); and (7) increased endoplasmic reticular stress and the unfolded protein response in endothelial cells. We also review the literature on studies of drugs that inhibit RAGE signaling in other diseases (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), or vasodilators developed for idiopathic pulmonary arterial hypertension that have been tested on cell culture systems, animal models of COPD, and/or smokers and COPD patients.
88 citations
TL;DR: In this article, the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab is assessed.
Abstract: Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab Inflammation and autoimmunity are established as important in PAH pathophysiology One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman's disease, there have been case reports of regression of PAH with tocilizumab TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR) Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP) If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy
65 citations
TL;DR: Balloon pulmonary angioplasty was safe, with one pulmonary vascular injury and subsequent self-limiting pulmonary bleeding as the only complication, and World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, and pulmonary arterial compliance improved, and NT-proBNP concentrations declined in 9/10 patients.
Abstract: Symptomatic patients with residual pulmonary perfusion defects or vascular lesions but no pulmonary hypertension at rest are diagnosed with chronic thromboembolic disease (CTED). Balloon pulmonary ...
61 citations
TL;DR: A primary role of the microcirculation in the pathogenesis and prognosis of ARDS after sepsis is supported, and the combination of biologic and clinical markers may make it possible to segregate patients with ARDS into hypo- versus hyper-inflammatory phenotypes that may have implications for therapeutic responses to fluid therapy.
Abstract: Experimental models of sepsis in small and large animals and a variety of in vitro preparations have established several basic mechanisms that drive endothelial injury. This review is focused on wh...
55 citations
TL;DR: The current status of the serotonin hypothesis is reviewed, potential and novel therapeutic targets are discussed, and potential targets for novel therapies for PAH are discussed.
Abstract: Increased synthesis of serotonin and/or activity of serotonin in pulmonary arteries has been implicated in the pathobiology of pulmonary arterial hypertension (PAH). The incidence of PAH associated with diet pills such as aminorex, fenfluramine, and chlorphentermine initially led to the "serotonin hypothesis of pulmonary hypertension." Over the last couple of decades there has been an accumulation of convincing evidence that targeting serotonin synthesis or signaling is a novel and promising approach to the development of novel therapies for PAH. Pulmonary endothelial serotonin synthesis via tryptophan hydroxlase 1 (TPH1) is increased in patients with PAH and serotonin can act in a paracrine fashion on underlying pulmonary arterial smooth muscle cells (PASMCs), In humans, serotonin can enter PASMCs via the serotonin transporter (SERT) or activate the 5-HT1B receptor; 5-HT1B activation and SERT activity cooperate to induce PASMC contraction and proliferation via activation of downstream proliferative and contractile signaling pathways. Here we will review the current status of the serotonin hypothesis and discuss potential and novel therapeutic targets.
53 citations
TL;DR: Findings provide, for the first time, support for the therapeutic strategy recommended by current guidelines, riociguat for inoperable patients with chronic thromboembolic pulmonary hypertension.
Abstract: Riociguat is the treatment of choice for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). We addressed here whether additional balloon pulmonary angioplasty (BPA) pro...
53 citations
TL;DR: This paper will review stem and progenitor cell definitions and highlight several recent papers purporting to have identified resident vascular endothelial stem and PROGenitor cells.
Abstract: The capacity of existing blood vessels to give rise to new blood vessels via endothelial cell sprouting is called angiogenesis and is a well-studied biologic process. In contrast, little is known about the mechanisms for endothelial cell replacement or regeneration within established blood vessels. Since clear definitions exist for identifying cells with stem and progenitor cell properties in many tissues and organs of the body, several groups have begun to accumulate evidence that endothelial stem and progenitor cells exist within the endothelial intima of existing blood vessels. This paper will review stem and progenitor cell definitions and highlight several recent papers purporting to have identified resident vascular endothelial stem and progenitor cells.
49 citations
TL;DR: The aim of this review is to provide an overview of the current knowledge on the effects of levosimendan in pulmonary hypertension and right heart failure.
Abstract: Pulmonary hypertension is a multifactorial disease with a high morbidity and mortality. Right ventricular function is the most important predictor of morbidity and mortality in patients suffering from pulmonary hypertension, but currently there are no approved treatments directly supporting the failing right ventricle. Levosimendan is a calcium sensitizing agent with inotropic, pulmonary vasodilatory, and cardioprotective properties. Given its pharmacodynamic profile, levosimendan could be a potential novel agent for the treatment of right ventricular failure caused by pulmonary hypertension. The aim of this review is to provide an overview of the current knowledge on the effects of levosimendan in pulmonary hypertension and right heart failure.
46 citations
TL;DR: The present evidence for an inflammatory component in PH disease is discussed with a specific focus on the potential role of the endothelium in this scenario and future avenues of experimental investigation which may lead to novel therapeutic interventions are highlighted.
Abstract: While pulmonary hypertension (PH) has traditionally not been considered as a disease that is directly linked to or, potentially, even caused by inflammation, a rapidly growing body of evidence has ...
40 citations
TL;DR: Mutation of genes encodingPiezo channels are also associated with hereditary human diseases, thus highlighting the critical role of Piezo channels in both tissue homeostasis and disease.
Abstract: Piezo channels are deemed to constitute one of the most important family of mechanosensing ion channels since their discovery in 2010. With recent advances in identifying their topological structure and the discovery of the agonist Yoda1 as well as the specific inhibitor GsMTx4, it is now possible to study the mechanisms by which Piezo channels are involved in physiological and pathophysiological processes. During embryonic cardiovascular development, Piezo1 senses shear stress and promotes vasculature growth. In adult mice, Piezo1 mediates the release of nitric oxide and ATP from endothelial cells to regulate blood pressure. Piezo channels also play a crucial role in cell differentiation and tissue homeostasis by exquisite mechanical force sensing. Piezo channels are also abundantly expressed in lung tissues. As the lung is exposed to complex pulmonary hemodynamics and respiratory mechanics, cells in the lung, such as microvascular endothelial cells, bear mechanical forces from blood flow shear, pulsatile strain, static pressure, and cyclic stretch due to respiratory movement. These mechanical stimuli are involved in a serial of physiological function and pathophysiological processes of the lung, many of which Piezo channels may be the key player. Mutation of genes encoding Piezo channels are also associated with hereditary human diseases, thus highlighting the critical role of Piezo channels in both tissue homeostasis and disease.
TL;DR: An overview of the clinical aspects of ACD/MPV is provided, including guidance for clinicians, and ongoing research into the complex molecular mechanism causing this severe lung disorder is reviewed.
Abstract: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal disorder mainly involving the vascular development of the lungs. Since its first description, significant achievements in research have led to a better understanding of the underlying molecular mechanism of ACD/MPV and genetic studies have identified associations with genomic alterations in the locus of the transcription factor FOXF1. This in turn has increased the awareness among clinicians resulting in over 200 cases reported so far, including genotyping of patients in most recent reports. Collectively, this promoted a better stratification of the patient group, leading to new perspectives in research on the pathogenesis. Here, we provide an overview of the clinical aspects of ACD/MPV, including guidance for clinicians, and review the ongoing research into the complex molecular mechanism causing this severe lung disorder.
TL;DR: The aim of this study was to estimate the incidence and risk factors of CTEPH in a cohort with first venous thromboembolism (VTE), a population-based cohort study of patients with first VTE and no active cancer in England between 2001 and 2012.
Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of unresolved organised pulmonary emboli/thrombi obstructing the major pulmonary arteries. The aim of this study was to estimate the incidence and risk factors of CTEPH in a cohort with first venous thromboembolism (VTE). This was a population-based cohort study of patients with first VTE and no active cancer in England between 2001 and 2012. CTEPH was assessed using a rigorous case-ascertainment algorithm. Risk factors for CTEPH were studied using a nested case-control approach by matching CTEPH cases to VTE patients without CTEPH. Adjusted odds ratios (OR) of comorbidities were estimated from conditional logistic regression. During 81,413 person-years of follow-up among 23,329 patients with first VTE (mean follow-up 3.5 years; maximum 11.0 years) 283 patients were diagnosed with CTEPH (incidence rate 3.5 per 1000 person-years); cumulative incidence was 1.3% and 3.3% at 2 and 10 years after pulmonary embolism, and 0.3% and 1.3% following deep vein thrombosis (DVT), respectively. Risk factors for CTEPH included age over 70, OR 2.04 (95% CI 1.23 to 3.38), female gender, 1.44 (1.06 to 1.94), pulmonary embolism at first VTE, 3.11 (2.23 to 4.35), subsequent pulmonary embolism and DVT, 3.17 (2.02 to 4.96) and 2.46 (1.34 to 4.51) respectively, chronic obstructive pulmonary disease 3.17 (2.13 to 4.73), heart failure 2.52 (1.76 to 3.63) and atrial fibrillation, 2.42 (1.71 to 3.42). CTEPH develops most commonly after pulmonary embolism and less frequently after DVT. Awareness of risk factors may increase referrals to specialised centres for confirmation of CTEPH and initiation of specific treatment.
TL;DR: Therapeutic strategies aimed at restoring sinus rhythm may represent an important goal in PAH patients and SSc-PAH with AA had the worst prognosis.
Abstract: Atrial arrhythmia (AA) occurrence in pulmonary arterial hypertension (PAH) may determine clinical deterioration and affect prognosis. In this study we assessed AA incidence in idiopathic (IPAH) and...
TL;DR: Off-label use of oral riociguat may be considered in selected children with severe PAH, after a marked decrease in PVR/SVR and transpulmonary pressure gradients, in RV hypertrophy, PA acceleration time, and left ventricular-eccentricity index.
Abstract: Riociguat has been approved for use in adults with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension. No clinical data on its therapeutic use in children with P...
TL;DR: RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy, and functional analysis of an RNF213 variant using mouse models suggests EC dysfunction.
Abstract: Ring finger 213 ( RNF213) is a susceptibility gene for moyamoya disease (MMD), a progressive cerebrovascular disease. Recent studies suggest that RNF213 plays an important role not only in MMD, but also in extracranial vascular diseases, such as pulmonary hypertension (PH). In this study, we undertook genetic screening of RNF213 in patients with PH and performed functional analysis of an RNF213 variant using mouse models. Direct sequencing of the exons in the C-terminal region of RNF213, where MMD-associated mutations are highly clustered, and of the entire coding exons of BMPR2 and CAV1, the causative genes for PH, was performed in 27 Japanese patients with PH. Two MMD-associated rare variants (p.R4810K and p.A4399T) in RNF213 were identified in two patients, three BMPR2 mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no CAV1 mutations were identified. To test the effect of the RNF213 variants on PH, vascular endothelial cell (EC)-specific Rnf213 mutant transgenic mice were exposed to hypoxia. Overexpression of the EC-specific Rnf213 mutant, but neither Rnf213 ablation nor EC-specific wild-type Rnf213 overexpression, aggravated the hypoxia-induced PH phenotype (high right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels). Under hypoxia, electron microscopy showed unique EC detachment in pulmonary vessels, and western blots demonstrated a significant reduction in caveolin-1 (encoded by CAV1), a key molecule involved in EC functions, in lungs of EC-specific Rnf213 mutant transgenic mice, suggestive of EC dysfunction. RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy.
TL;DR: Elevated pulmonary ET-1 is implicate as a marker of, and a potential contributor to, development of Cpc-PH in this population of patients with preserved left ventricular ejection fraction.
Abstract: Pulmonary hypertension complicating left heart disease (PH-LHD) is associated with increased morbidity and mortality, especially in patients who develop combined pre- and post-capillary PH (Cpc-PH)...
TL;DR: This review focuses on summarizing natural plant compounds with therapeutic properties in PAH, according to the extracts, fractions, and pure compounds from plants into categories, hoping it to be helpful for basic research and clinical application.
Abstract: Pulmonary arterial hypertension (PAH) is a severe disease characterized by progressive remodeling of distal pulmonary arteries and persistent elevation of pulmonary vascular resistance (PVR), which leads to right ventricular dysfunction, heart failure, and eventually death. Although treatment responsiveness for this disease is improving, it continues to be a life-threatening condition. With the clinical efficacy of natural plant products being fully confirmed by years of practice, more and more recognition and attention have been obtained from the international pharmaceutical industry. Moreover, studies over the past decades have demonstrated that drugs derived from natural plants show unique advantages and broad application prospects in PAH treatment, not to mention the historical application of Chinese traditional medicine in cardiopulmonary diseases. In this review, we focus on summarizing natural plant compounds with therapeutic properties in PAH, according to the extracts, fractions, and pure compounds from plants into categories, hoping it to be helpful for basic research and clinical application.
TL;DR: Combination therapy was associated with a significant improvement in both RV and LV function as assessed by CMR-derived strain and SR, and correlated with improvements in known prognostic markers of PAH.
Abstract: The aim of this study was to evaluate the effect of upfront combination therapy with ambrisentan and tadalafil on left ventricular (LV) and right ventricular (RV) function in patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). LV and RV peak longitudinal and circumferential strain and strain rate (SR), which consisted of peak systolic SR (SRs), peak early diastolic SR (SRe), and peak atrial-diastolic SR (SRa) were analyzed using cardiac magnetic resonance imaging (CMRI) data from the recently published ATPAHSS-O trial (ambrisentan and tadalafil upfront combination therapy in SSc-PAH). Twenty-one patients completed the study protocol. Measures of RV systolic function (RV free wall [RVFW] peak longitudinal strain [pLS], RVFW peak longitudinal SRs [pLSRs]) and RV diastolic function (RVFW peak longitudinal SRa [pLSRa], RVFW peak circumferential SRe) were improved after treatment. LV systolic function (LV peak global longitudinal strain [pGLS]) and diastolic function (LV peak global longitudinal SRe [pGLSRe]) were also significantly improved at follow-up. Increased 6-min walk distance was significantly correlated with RVFW pLS and pLSRs, while the decrease in N-terminal pro-brain natriuretic peptide was correlated with LV pGLS. Increased cardiac index was associated with improved LV pGLSRe, and reduction in mean right atrial pressure was correlated with improved RVFW pLS and pLSRa. Combination therapy was associated with a significant improvement in both RV and LV function as assessed by CMR-derived strain and SR. Importantly, the improvement in RV and LV strain and SR correlated with improvements in known prognostic markers of PAH. (Approved by clinicaltrials.gov [NCT01042158] before patient recruitment.).
TL;DR: Children with PH have increased risk of perioperative complications; cardiac arrest and death occur more frequently in patients with severe PH and those undergoing thoracic procedures and lends itself to further prospective studies.
Abstract: Prior limited research indicates that children with pulmonary hypertension (PH) have higher rates of adverse perioperative outcomes when undergoing non-cardiac procedures and cardiac catheterizations. We examined a single-center retrospective cohort of children with active or pharmacologically controlled PH who underwent cardiac catheterization or non-cardiac surgery during 2006–2014. Preoperative characteristics and perioperative courses were examined to determine relationships between the severity or etiology of PH, type of procedure, and occurrence of major and minor events. We identified 77 patients who underwent 148 procedures at a median age of six months. The most common PH etiologies were bronchopulmonary dysplasia (46.7%), congenital heart disease (29.9%), and congenital diaphragmatic hernia (14.3%). Cardiac catheterizations (39.2%), and abdominal (29.1%) and central venous access (8.9%) were the most common procedures. Major events included failed planned extubation (5.6%), postoperative cardiac...
TL;DR: Latvian PAH patients had the fourth lowest and CTEPH patients the lowest one-year survival rate among European adult PH registries and it would be desirable to combine these registries to produce more reliable and high-quality study results.
Abstract: Patient registries are a valuable tool in the research of rare conditions such as pulmonary hypertension (PH). We report comprehensive hemodynamic and survival data of 174 patients with pulmonary a...
TL;DR: Riociguat was well tolerated and improved 6-min walking distance (6MWD), World Health Organization functional class (WHO FC), and other efficacy parameters; 6MWD and WHO FC improvements were sustained over two years in the open-label extension, PATENT-2.
Abstract: In patients with portopulmonary hypertension (n = 13) included in the 12-week randomized placebo-controlled PATENT-1 trial, riociguat was well tolerated and improved 6-min walking distance (6MWD), ...
TL;DR: Developing and validate a set of algorithms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and electronic medical records (EMR), to identify patients with PAH and found that claims-based algorithms that included ICD- 9-CM codes, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medications better-identified patients withPAH.
Abstract: Administrative claims studies do not adequately distinguish pulmonary arterial hypertension (PAH) from other forms of pulmonary hypertension (PH). Our aim is to develop and validate a set of algorithms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and electronic medical records (EMR), to identify patients with PAH. From January 2012 to August 2015, the EMRs of patients with ICD-9-CM codes for PH with an outpatient visit at the University of Texas Medical Branch were reviewed. Patients were divided into PAH or non-PAH groups according to EMR encounter diagnosis. Patient demographics, echocardiography, right heart catheterization (RHC) results, and PAH-specific therapies were assessed. RHC measurements were reviewed to categorize cases as hemodynamically determined PAH or not PAH. Weighted sensitivity, specificity, and positive and negative predictive values were calculated for the developed algorithms. A logistic regression analysis was conducted to determine how well the algorithms performed. External validation was performed at the University of Virginia Health System. The cohort for the development algorithms consisted of 683 patients with PH, PAH group (n = 191) and non-PAH group (n = 492). A hemodynamic diagnosis of PAH determined by RHC was recorded in the PAH (26%) and non-PAH (3%) groups. The positive predictive value for the algorithm that included ICD-9-CM and PAH-specific medications was 66.9% and sensitivity was 28.2% with a c-statistic of 0.66. The positive predictive value for the EMR-based algorithm that included ICD-9-CM, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medication was 69.4% and a c-statistic of 0.87. A validation cohort of 177 patients with PH examined from August 2015 to August 2016 using EMR-based algorithms yielded a similar positive predictive value of 62.5%. In conclusion, claims-based algorithms that included ICD-9-CM codes, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medications better-identified patients with PAH than ICD-9-CM codes alone.
TL;DR: Results indicate that IL-6 trans-signaling contributes to pulmonary arterial cell migration and CH-induced PH, and mice that received the IL- 6 trans-Signaling-specific inhibitor sgp130Fc showed attenuation ofCH-induced increases in right ventricular systolic pressure,right ventricular and pulmonary arterials remodeling as compared to vehicle (saline)-treated control mice.
Abstract: Interleukin-6 (IL-6) is a pleotropic cytokine that signals through the membrane-bound IL-6 receptor (mIL-6R) to induce anti-inflammatory ("classic-signaling") responses. This cytokine also binds to the soluble IL-6R (sIL-6R) to promote inflammation ("trans-signaling"). mIL-6R expression is restricted to hepatocytes and immune cells. Activated T cells release sIL-6R into adjacent tissues to induce trans-signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. Reports show that IL-6 is produced by pulmonary arterial smooth muscle cells (PASMCs) exposed to hypoxia in culture as well as the medial layer of the pulmonary arteries in mice exposed to chronic hypoxia (CH), and IL-6 knockout mice are protected from CH-induced pulmonary hypertension (PH). IL-6 has the potential to contribute to a broad array of downstream effects, such as cell growth and migration. CH-induced PH is associated with increased proliferation and migration of PASMCs to previously non-muscularized vessels of the lung. We tested the hypothesis that IL-6 trans-signaling contributes to CH-induced PH and arterial remodeling. Plasma levels of sgp130 were significantly decreased in mice exposed to CH (380 mmHg) for five days compared to normoxic control mice (630 mmHg), while sIL-6R levels were unchanged. Consistent with our hypothesis, mice that received the IL-6 trans-signaling-specific inhibitor sgp130Fc, a fusion protein of the soluble extracellular portion of gp130 with the constant portion of the mouse IgG1 antibody, showed attenuation of CH-induced increases in right ventricular systolic pressure, right ventricular and pulmonary arterial remodeling as compared to vehicle (saline)-treated control mice. In addition, PASMCs cultured in the presence of IL-6 and sIL-6R showed enhanced migration but not proliferation compared to those treated with IL-6 or sIL-6R alone or in the presence of sgp130Fc. These results indicate that IL-6 trans-signaling contributes to pulmonary arterial cell migration and CH-induced PH.
TL;DR: Loss of cilia length regulation upon cytokine stimulation as part of the endothelial dysfunction in PAH was identified, as application of fluid shear stress led to increased cilialength in the PAH endothelium.
Abstract: Pulmonary arterial hypertension (PAH) is a syndrome characterized by progressive lung vascular remodelling, endothelial cell (EC) dysfunction, and excessive inflammation. The primary cilium is a sensory antenna that integrates signalling and fine tunes EC responses to various stimuli. Yet, cilia function in the context of deregulated immunity in PAH remains obscure. We hypothesized that cilia function is impaired in ECs from patients with PAH due to their inflammatory status and tested whether cilia length changes in response to cytokines. Primary human pulmonary and mouse embryonic EC were exposed to pro- (TNFα, IL1β, and IFNγ) and/or anti-inflammatory (IL-10) cytokines and cilia length was quantified. Chronic treatment with all tested inflammatory cytokines led to a significant elongation of cilia in both control human and mouse EC (by ∼1 µm, P < 0.001). This structural response was PKA/PKC dependent. Intriguingly, withdrawal of the inflammatory stimulus did not reduce cilia length. IL-10, on the other hand, blocked and reversed the pro-inflammatory cytokine-induced cilia elongation in healthy ECs, but did not influence basal length. Conversely, primary cilia of ECs from PAH patients were significantly longer under basal conditions compared to controls (1.86 ± 0.02 vs. 2.43 ± 0.08 µm, P = 0.002). These cilia did not elongate further upon pro-inflammatory stimulation and anti-inflammatory treatment did not impact cilia length. The missing length modulation was specific to cytokine stimulation, as application of fluid shear stress led to increased cilia length in the PAH endothelium. We identified loss of cilia length regulation upon cytokine stimulation as part of the endothelial dysfunction in PAH.
TL;DR: This review summarizes the current understanding of stiffness-dependent regulation of pulmonary EC permeability and inflammation, and discusses potential implication of pulmonary vascular stiffness alterations at macro- and microscale in development and modulation of ALI and PH.
Abstract: The maintenance of endothelial barrier integrity is absolutely essential to prevent the vascular leak associated with pneumonia, pulmonary edema resulting from inhalation of toxins, acute elevation...
TL;DR: The risk for new PAV Ms to develop, small PAVMs to become large, and previously embolized PAVm to require further intervention remains throughout childhood, and children with HHT require continued follow-up until adulthood.
Abstract: Pulmonary arteriovenous malformations (PAVMs) often occur in children with hereditary hemorrhagic telangiectasia (HHT). A 14-year longitudinal study of PAVMs in children with HHT was undertaken to ...
TL;DR: This review analyzed the advantages and disadvantages of the two techniques and discussed pre-existing and novel forms of analysis where echocardiography and CMRI can be used to examine atrial, ventricular, and interventricular function in patients with PH at rest and under stress.
Abstract: Pulmonary hypertension (PH) is a progressive illness characterized by elevated pulmonary artery pressure; however, the main cause of mortality in PH patients is right ventricular (RV) failure. Historically, improving the hemodynamics of pulmonary circulation was the focus of treatment; however, it is now evident that cardiac response to a given level of pulmonary hemodynamic overload is variable but plays an important role in the subsequent prognosis. Non-invasive tests of RV function to determine prognosis and response to treatment in patients with PH is essential. Although the right ventricle is the focus of attention, it is clear that cardiac interaction can cause left ventricular dysfunction, thus biventricular assessment is paramount. There is also focus on the atrial chambers in their contribution to cardiac function in PH. Furthermore, there is evidence of regional dysfunction of the two ventricles in PH, so it would be useful to understand both global and regional components of dysfunction. In order to understand global and regional cardiac function in PH, the most obvious non-invasive imaging techniques are echocardiography and cardiac magnetic resonance imaging (CMRI). Both techniques have their advantages and disadvantages. Echocardiography is widely available, relatively inexpensive, provides information regarding RV function, and can be used to estimate RV pressures. CMRI, although expensive and less accessible, is the gold standard of biventricular functional measurements. The advent of 3D echocardiography and techniques including strain analysis and stress echocardiography have improved the usefulness of echocardiography while new CMRI technology allows the measurement of strain and measuring cardiac function during stress including exercise. In this review, we have analyzed the advantages and disadvantages of the two techniques and discuss pre-existing and novel forms of analysis where echocardiography and CMRI can be used to examine atrial, ventricular, and interventricular function in patients with PH at rest and under stress.
TL;DR: Right ventricular load-adaptability echocardiographic indices do not appear to capture the increased risk of negative outcomes at one year associated with SSc-PAH, and patients with IPAH responded better to therapy in terms of reduction of right ventricular areas.
Abstract: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is associated with worse outcome than idiopathic pulmonary arterial hypertension (IPAH), potentially due to worse right ventricular ...
TL;DR: Evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and limitations of the models that are used to study these effects are discussed.
Abstract: Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH.