Severe Asthma or Chronic Obstructive Pulmonary Disease with Eosinophilic Inflammation? From Uncertainty to Remission under Anti IL-5R Therapy.

Background and Objectives: Severe adult-onset eosinophilic asthma and COPD with eosinophilic inflammation are two entities with a similar clinical course and are sometimes difficult to differentiate in clinical practice, especially in patients with a history of smoking. Anti-IL-5 or -IL-5R biological therapy has been shown to be highly effective in severe eosinophilic asthma but has not demonstrated significant benefit in patients with COPD with the eosinophilic phenotype. Our aim was to illustrate this issue in the form of a case report. Materials and Methods: We present the case of a 67-year-old patient who is a former smoker with late-onset severe uncontrolled asthma (ACT score < 15) who experienced frequent exacerbations requiring treatment with systemic corticosteroids. The patient's lung function gradually worsened to a nadir FEV1 = 18%, despite a high dose of ICS in combination with a LABA and intermittent courses of OCS, with negative allergic skin-tests, but with high blood eosinophils level. Biological treatment with an anti-IL5R monoclonal antibody (benralizumab) was initiated, despite the difficulty in the differential diagnosis between asthma and COPD with eosinophilic inflammation. Results: The patient's evolution was favorable; clinical remission was effectively achieved with significant improvement in lung function (FEV1 > 100%), but with persistence of residual mild fixed airway obstructive dysfunction (FEV1/FVC < 0.7). The therapeutic response has been maintained to date. Conclusions: Benralizumab was shown to be very effective in a patient with late-onset severe eosinophilic asthma presenting features of chronic obstructive disease-habitual exposure to tobacco and inhaled noxious substances, and persistent airflow limitation on spirometry.

The relationship between periodic limb movement during sleep and dyslipidaemia in patients with obstructive sleep apnea.

Periodic limb movements during sleep and obstructive sleep apnea are both associated with increased sympathetic tone, and have been proposed as risk factors for heart diseases and, in particular, cardiovascular disease. As sympathetic system activation may lead to dyslipidaemia, periodic limb movements during sleep could be an additional risk factor for cardiovascular disease in patients with obstructive sleep apnea. The aim of the study was to determine whether the presence of periodic limb movements during sleep affects serum lipid levels in obstructive sleep apnea. Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non- high-density lipoprotein cholesterol and triglyceride levels were investigated in 4138 patients with obstructive sleep apnea in the European Sleep Apnea Database (ESADA) cohort, divided into those with periodic limb movements during sleep index ≥ 15 per hr (n = 628) and controls (n = 3510). ANCOVA adjusted for age, sex, body mass index, apnea-hypopnea index, alcohol intake, smoking status, diabetes, insomnia and study site was used to assess differences in lipids between periodic limb movements during sleep and controls. Patients with periodic limb movements during sleep (24% female, 54.4 ± 12.1 years, body mass index 31.9 ± 5.8 kg m-2 , apnea-hypopnea index 36.7 ± 25.4 per hr) had higher triglyceride (1.81 ± 1.04 versus 1.69 ± 0.90 mmol L-1 , p = 0.002) and lower high-density lipoprotein cholesterol (1.19 ± 0.34 versus 1.24 ± 0.37 mmol L-1 , p = 0.002) levels, whilst there was no difference in either total cholesterol (4.98 ± 1.10 versus 4.94 ± 1.07 mmol L-1 ), low-density lipoprotein cholesterol (3.04 ± 0.96 versus 2.98 ± 0.98 mmol L-1 ) or non- high-density lipoprotein cholesterol (3.78 ± 1.10 versus 3.70 ± 1.05 mmol L-1 ) concentrations (all p > 0.05). The results remained unchanged after most sensitivity analyses. Patients with obstructive sleep apnea with periodic limb movements during sleep had more prevalent cardiovascular disease (11% versus 6%, p < 0.01). Periodic limb movements during sleep in obstructive sleep apnea is associated with dyslipidaemia independently of important confounders. Our results highlight periodic limb movements during sleep as an additional risk factor for cardiovascular disease in obstructive sleep apnea.

Epithelial alarmins: a new target to treat chronic respiratory diseases.

INTRODUCTION: In response to injury, epithelial cells release alarmins including thymic stromal lymphopoietin (TSLP), high mobility group-box-1 (HMGB1), interleukin (IL)-33 and -25 that can initiate innate immune responses. These alarmins are recognized as activators of T2-immune responses characteristic for asthma, but recent evidence highlighted their role in non-T2 inflammation, airway remodeling, and pulmonary fibrosis making them an attractive therapeutic target for chronic respiratory diseases (CRD). AREAS COVERED: In this review, firstly we discuss the role of TSLP, IL-33, IL-25, and HMGB1 in the pathogenesis of asthma, COPD, idiopathic pulmonary fibrosis, and cystic fibrosis according to the published data. In the second part, we summarize the current evidence concerning the efficacy of the antialarmin therapies in CRD. Recent clinical trials showed that anti-TSLP and IL-33/R antibodies can improve severe asthma outcomes. Blocking the IL-33-mediated pathway decreased the exacerbation rate in COPD patients with more important benefit for former-smokers. EXPERT OPINION: Despite progress in the understanding of the alarmins' role in the pathogenesis of CRD, all their mechanisms of action are not yet identified. Blocking IL-33 and TSLP pathways offers an interesting option to treat severe asthma and COPD, but future investigations are needed to establish their place in the treatment strategies.

Manifesto on united airways diseases (UAD): an Interasma (global asthma association - GAA) document.

OBJECTIVE: The large amount of evidence and the renewed interest in upper and lower airways involvement in infectious and inflammatory diseases has led Interasma (Global Asthma Association) to take a position on United Airways Diseases (UAD). METHODS: Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto developed by Interasma scientific network (INES) members. RESULTS: The manifesto describes the evidence gathered to date and defines, states, advocates, and proposes issues on UAD (rhinitis, rhinosinusitis and nasal polyposis), and concomitant/comorbid lower airways disorders (asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, obstructive sleep apnoea) with the aim of challenging assumptions, fostering commitment, and bringing about change. UAD refers to clinical pictures characterized by the coexistence of upper and lower airways involvement, driven by a common pathophysiological mechanism, leading to a greater burden on patient's health status and requiring an integrated diagnostic and therapeutic plan. The high prevalence of UAD must be taken into account. Upper and lower airways diseases influence disease control and patient's quality of life. CONCLUSIONS: Patients with UAD need to have a timely and adequate diagnosis, treatment, and, when recommended, referral for management in a specialized center. Diagnostic testing including skin prick or serum specific IgE, lung function, fractional exhaled nitric oxide (FeNO), polysomnography, allergen-specific immunotherapies, biological therapies and home based continuous positive airway pressure (CPAP) whenever these are recommended, should be part of the management plan for UAD. Education of medical students, physicians, health professionals, patients and caregivers on the UAD is needed.

Asthma and obstructive sleep apnoea in adults and children - an up-to-date review.

Obstructive sleep apnoea (OSA) and asthma are two common respiratory disorders in children and adults. Apart from common risk factors, such as obesity, gastroesophageal reflux disease and allergic rhinitis, emerging evidence suggest that the two diseases may complicate the clinical course of each other. On one hand, OSA modifies asthmatic airway inflammation and is associated with poor asthma control. On the other hand, asthma and its medications increase the collapsibility of the upper airways contributing to the development and worsening of OSA. The overnight respiratory symptoms of OSA and asthma are often similar, and an inpatient polysomnography is often necessary for a proper diagnosis, especially in children. Continuous positive pressure, the gold standard treatment for OSA can improve asthma control in patients suffering from both diseases. However, there is limited evidence how anti-asthma medications act in the same patients. Nevertheless, adenotonsillectomy seems to be effective in children with concomitant asthma and OSA. This review summarises the evidence for the bidirectional link between asthma and OSA, focuses on diagnostic and therapeutic challenges and highlights the need for further research.

Triglyceride-Glucose Index in Non-Diabetic, Non-Obese Patients with Obstructive Sleep Apnoea.

Obstructive sleep apnoea (OSA) is associated with increased insulin resistance. Triglyceride-glucose index (TyG) is a simple marker of insulin resistance; however, it has been investigated only by two studies in OSA. The aim of this study was to evaluate TyG in non-diabetic, non-obese patients with OSA. A total of 132 patients with OSA and 49 non-OSA control subjects were included. Following a diagnostic sleep test, fasting blood was taken for the analysis of the lipid profile and glucose concentrations. TyG was calculated as ln(triglyceride [mg/dL] × glucose [mg/dL]/2). Comparison analyses between OSA and control groups were adjusted for age, gender, body mass index (BMI) and smoking. TyG was higher in men (p < 0.01) and in ever-smokers (p = 0.02) and it was related to BMI (ρ = 0.33), cigarette pack-years (ρ = 0.17), apnoea-hypopnoea index (ρ = 0.38), oxygen desaturation index (ρ = 0.40), percentage of total sleep time spent with oxygen saturation below 90% (ρ = 0.34), and minimal oxygen saturation (ρ = -0.29; all p < 0.05). TyG values were significantly higher in OSA (p = 0.02) following adjustment for covariates. OSA is independently associated with higher TyG values which are related to disease severity in non-obese, non-diabetic subjects. However, the value of TyG in clinical practice should be evaluated in follow-up studies in patients with OSA.

The Burden of Associated Comorbidities in Patients with Obstructive Sleep Apnea-Regional Differences in Two Central-Eastern European Sleep Centers.

BACKGROUND: Obstructive sleep apnea (OSA) is usually associated with cardiovascular and cerebrovascular disease, metabolic syndrome and depression. Data on relevant OSA-associated comorbidities in Central-European populations are scarce. The aim of this study was to compare the prevalence of comorbidities in two OSA cohorts from Hungary and Romania. METHODS: Data from 588 (282 from Hungary, 306 from Romania) untreated patients with OSA were retrospectively analyzed. The prevalence rates of hypertension, diabetes, dyslipidemia, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), osteoporosis, cerebrovascular and cardiovascular disease, arrhythmia and depression were compared between the two populations following adjustment for demographics, body mass index, smoking history, comorbidities and sleep parameters. RESULTS: The prevalence rates of hypertension, arrhythmia, cerebrovascular and cardiovascular disease, diabetes and COPD in the whole study population were directly related to the severity of OSA. We found an inverse correlation between the prevalence of osteoporosis and OSA severity (all p < 0.05). Following adjustment, the prevalence of dyslipidemia was higher in the Hungarian cohort, whilst the prevalence of asthma, cardiovascular and cerebrovascular diseases was higher in the Romanian cohort (all p < 0.05). CONCLUSIONS: There was no difference in the prevalence rate of most comorbidities in patients with OSA from the two cohorts, except for dyslipidemia, asthma, cardiovascular and cerebrovascular disease.

Current opinions for the management of asthma associated with ear, nose and throat comorbidities.

Ear, nose and throat (ENT) comorbidities are common in patients with asthma and are frequently associated with poorer asthma outcomes. All these comorbidities are "treatable traits" in asthma. Identification and management of these disorders may spare medication usage and contribute to improved asthma control and quality of life, and a decrease in exacerbation rates.This review summarises recent data about the prevalence, clinical impact and treatment effects of ENT comorbidities in asthma including allergic rhinitis, chronic rhinosinusitis with and without nasal polyposis, aspirin-exacerbated respiratory disease, obstructive sleep apnoea and vocal cord dysfunction.Many of these comorbidities are possible to be managed by the pulmonologist, but the collaboration with the ENT specialist is essential for patients with chronic rhinosinusitis or vocal cord dysfunction. Further rigorous research is needed to study the efficacy of comorbidity treatment to improve asthma outcomes, in particular with the development of biotherapies in severe asthma that can also be beneficial in some ENT diseases.

SAS score: Targeting high-specificity for efficient population-wide monitoring of obstructive sleep apnea.

PROPOSAL: This paper investigates a novel screening tool for Obstructive Sleep Apnea Syndrome (OSAS), which aims at efficient population-wide monitoring. To this end, we introduce SASscore which provides better OSAS prediction specificity while maintaining a high sensitivity. METHODS: We process a cohort of 2595 patients from 4 sleep laboratories in Western Romania, by recording over 100 sleep, breathing, and anthropometric measurements per patient; using this data, we compare our SASscore with state of the art scores STOP-Bang and NoSAS through area under curve (AUC), sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). We also evaluate the performance of SASscore by considering different Apnea-Hypopnea Index (AHI) diagnosis cut-off points and show that custom refinements are possible by changing the score's threshold. RESULTS: SASscore takes decimal values within the interval (2, 7) and varies linearly with AHI; it is based on standardized measures for BMI, neck circumference, systolic blood pressure and Epworth score. By applying the STOP-Bang and NoSAS questionnaires, as well as the SASscore on the patient cohort, we respectively obtain the AUC values of 0.69 (95% CI 0.66-0.73, p < 0.001), 0.66 (95% CI 0.63-0.68, p < 0.001), and 0.73 (95% CI 0.71-0.75, p < 0.001), with sensitivities values of 0.968, 0.901, 0.829, and specificity values of 0.149, 0.294, 0.359, respectively. Additionally, we cross-validate our score with a second independent cohort of 231 patients confirming the high specificity and good sensitivity of our score. When raising SASscore's diagnosis cut-off point from 3 to 3.7, both sensitivity and specificity become roughly 0.6. CONCLUSIONS: In comparison with the existing scores, SASscore is a more appropriate screening tool for monitoring large populations, due to its improved specificity. Our score can be tailored to increase either sensitivity or specificity, while balancing the AUC value.

Use of electronic cigarettes and alternative tobacco products among Romanian adolescents.

OBJECTIVES: To assess socio-demographic and smoking-related correlates of e-cigarette and alternative tobacco products (ATPs) use in a multi-ethnic group of adolescents in Tîrgu Mures, Romania. METHODS: The cross-sectional study included 1835 high school students from Tirgu Mures, Romania. Socio-demographic variables and data about smoking and e-cigarettes and ATP use were collected using an online questionnaire. Chi-square tests or one-way ANOVA were applied to compare never smokers, non-current smokers, and current smokers. Multiple logistic regression was conducted to determine the correlates of e-cigarettes and ATP use. RESULTS: The most frequently tried non-cigarette nicotine and tobacco products were e-cigarette (38.5 %), cigar (31.4 %) and waterpipe (21.1 %). Ever trying and current use of cigarettes were the most important correlates of e-cigarette and ATPs use. Sex, ethnicity, sensation seeking and perceived peer smoking were correlates of several ATPs use. CONCLUSIONS: The results of this study may inform the development of tailored tobacco control programs.

Rates and predictors of uncontrolled bronchial asthma in elderly patients from western Romania.

PURPOSE: Bronchial asthma (BA) is a chronic inflammatory disorder of the airways, featuring variable and often reversible airflow limitations. An accurate assessment of BA control is difficult in practice, especially in the elderly, requiring the assessment of several clinical and paraclinical parameters that are influenced not only by asthma, but also by comorbidities. The purpose of this study was to evaluate the predictors of uncontrolled BA in a group of elderly patients from western Romania. PATIENTS AND METHODS: We retrospectively evaluated 126 elderly patients (aged $ 65 years), who were consecutively evaluated in the Pulmonology Department of Victor Babes Hospital, Timisoara, Romania, between March 2009 and July 2012. We collected demographic data, performed pulmonary function testing and an asthma control test (ACT), and evaluated the level of BA control based on the 2012 Global Initiative for Asthma guidelines. Statistical processing of the data was done using the Epi Info and STATA programs. RESULTS: In our study group, 36 (29%) patients were men and 90 (71%) were women; their mean age was 74.42±8.32 years (range: 65-85 years). A total of 14.28% of patients were smokers. About 30.15% of patients had an ACT score <19, 54.76% had an ACT score 20-24, and 15.09% had an ACT of 25. Moreover, 59.52% had normal spirometry results. Infectious exacerbations were found in 58.73% of patients. A history of allergies was demonstrated in 48.41% of patients, 34.12% had occupational exposure, and 82.53% of patients were treated with inhaled corticosteroids. Our results showed that 30.15% of patients had uncontrolled BA. We found six predictive factors for uncontrolled BA: infectious exacerbation, occupational exposure, mixed (obstructive and restrictive) ventilatory dysfunction, persistent airway obstruction on spirometry, duration of disease in months, and current smoking status. Infectious exacerbations, persistent airway obstructions, and occupational exposure were the most powerful predictors. CONCLUSION: Elderly patients represent an important group that is at risk for developing uncontrolled BA. Predictors may identify those elderly patients with uncontrolled BA and facilitate early medical interventions.

Types of Interventions for Smoking Prevention and Cessation in Children and Adolescents.

Smoking among children and adolescents is a pressing public health issue that demands the development, improvement and implementation of programmes aimed at the prevention and cessation of smoking on a global scale. The objective of our article is to review the main types of interventions for smoking prevention and cessation among children and adolescents. These interventions are based on a wide variety of approaches and include school-based programmes, primary and secondary care-based interventions, programmes targeting parents and family, community-based programmes, social marketing programmes and media campaigns, legislative interventions and computer and other IT-based interventions. Generally, there is still a paucity of low level evidence regarding the efficacy of most smoking prevention and cessation programmes for children and adolescents except for a few particular types of interventions that are reasonably well documented.

Long-term effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea.

Obstructive sleep apnea (OSA) is often linked to high blood pressure and has a particularly high prevalence in patients with resistant hypertension. The effect of continuous positive airway pressure (CPAP) therapy on blood pressure (BP) values has been evaluated in several short-term clinical trials with conflicting results. Our aim was to investigate the role of long-term CPAP treatment in achieving BP control in patients who associate OSA and resistant hypertension. We have included in the study 33 patients with resistant hypertension, diagnosed with OSA in our sleep lab. Data was collected initially and after a mean follow-up period of 4 years. Patients were divided into 2 groups according to the use of CPAP therapy. Patients under CPAP therapy (n = 12) exhibited a higher reduction in both systolic and diastolic pressure and BP control was achieved in 75% of cases, while patients without CPAP treatment (n = 21) remained with refractory hypertension in proportion of 90.5%. A de-escalation of antihypertensive drug regimen by discontinuation of 1 or more drugs was observed in 41.6% (n = 5) of patients from CPAP group and in the other 33.4% (n = 4) the medication remained unchanged, but BP control was reached. Using a direct logistic regression model for examining the impact of different confounders on the probability of diagnosis of resistant hypertension at follow-up, the only statistically significant predictor found was the lack of CPAP usage.

Smoking as a predictor for loosing control of treated bronchial asthma.

AIM: Analysis of the factors involved in uncontrolled bronchial asthma (BA). MATERIAL AND METHOD: Between October 2007 and November 2008 we evaluated 584 consecutive patients, known and treated for BA, and collected general data, medical history, disease onset, spirometry, treatment duration, treatment, asthma control test (ACT). The association of variables was analyzed by calculating the odds ratio (OR) together with confidence intervals (CI) in a univariate analysis. The significant independent variables were utilized to create models of multivariate logistical analysis in order to identify the most important predictors. RESULTS: 584 patients, 162 males (27,74%), 422 females (72,26%), medium age 45,38 +/- 17,48 years (9-85), 14% smokers, ACT <19 (36,2%), 20-24 (48,8%), 25 (15%), 43,1% exacerbations, 4 predictors for uncontrolled BA: exacerbations OR 4,11, CI 3,30-7,48, p<0,001, professional exposure OR 2,29, CI 1,23-4,26, p=0,009, altered lung function on spirometry OR=1,18, CI 1,02-1,36, p=0,021 (obstruction OR 3,78 CI 1,76-7,78, p=0,0001), duration of disease (months) OR=1,02, CI 1,00-1,03, p=0,021, smoking OR 0,57, CI 0,26-0,71, p=0,012. CONCLUSIONS: More than 1/3 (36,2%) of treated asthmatic patients had uncontrolled asthma. Smoking is not among the predictors for lack of control.

Smoking cessation and prevention for young people--Romanian expertise.

INTRODUCTION: According to a National Study inside The European School Survey Project on Alcohol and other Drugs, 64% of schoolchildren aged 16 in Romania have ever smoked at least one cigarette. Starting 2005, volunteers from NGO "Aer Pur Romania (APR)" have become involved in European projects targeting smoke free schoolchildren and adolescents. METHODS: "Smoke-free class" competition project, was co-funded by EU, implemented first time in the school year 2004/2005 by the APR and Romanian National Anti- Drug Agency (RNDA) and was run annually ever since. The OBJECTIVE was smoking prevention among secondary school children aged 11-15. Classes decide to be a non-smoking class for a period of four months (at least 90% of class students decided to be non smokers during the program). The program was implemented in 5 counties in 2004/2005 and starting 2006 at national level. groups of 20-25 participants were given 6 classes about smoking induced harm, benefits of quitting smoking. Smoking status was determined in the first session by carbon monoxide (CO) measurement in exhaled air, than quitting smoking was encouraged and supported along sessions 2-5 and finally, with confirmation in session 6 of smoking status by CO. "Quit and Win" (Q&W) contest, aimed to encourage young smokers to stop smoking. Target group was 14-18 years old high school pupils, in 5 big towns of Romania. They had to refrain from smoking for 30 days. "I do not smoke" was a program funded by the Royal Embassy of Netherlands in Romania and was implemented by APR and RNDA, Romanian Ministry of Education and University of Medicine and Pharmacy of Cluj-Napoca. RESULTS: ASC involved 231 adolescents from 8 high schools that graduated the program (132 girls and 99 boys), 19 quitters (8.2%), 20 reducers and 48 participants tried to stop smoking at least once during the project. Six months evaluation showed 10 adolescents still abstinent and 4 still reducers. IDNS was done in 2006 with 27 classes aged 13/14 from Cluj-Napoca. Q&W was developed between 1 October- 30 November 2005, 6000 registration forms were distributed in 35 high schools from cities of Bucharest, Iasi, Cluj, Constanta and Timisoara. 67.3% of interviewed subjects registered for the contest, meaning 4038 persons, 24% current smokers and 76% never smokers. CONCLUSION: Tobacco prevention needs long term control measures, having joint governmental, NGO and academic institutions initiatives, to assist teenagers to quit and to help them not to start.

[New concepts in the pathogenesis and pathophysiology of COPD]. / Concepte actuale privind patogenia si fiziopatologia BPOC.

Chronic obstructive pulmonary disease (COPD) is characterized by the progressive, partially reversible air flow limitation which occurs in association with a chronic inflammatory reaction triggered by smoking or other inhalation noxes in predisposed subjects. Genetic predisposition and /or latent adenoviral infections are responsible for the exacerbation and perpetuation of the inflammatory response despite smoking cessation. Inflammation is further aggravated by a process of chromatinic remodelling which amplify the expression of pro-inflammatory genes. Besides the role of macrophages, neutrophils and /CD8+ T lymphocytes, the involvement of dendritic cells, epithelial cells and eosinophils within the airway inflammation has also been reported. The other two contributors to the COPD pathogenesis are the oxidative stress and the proteases-antiproteases imbalance. Both processes together with the inflammatory one are responsible for the parietal remodelling of the bronchioles and the appearance of emphysema, the latter being aggravated by the apoptosis of the alveolar cells. Another important pathophysiological concept within the natural evolution of COPD is the pulmonary endothelial dysfunction which might be responsible for the arterial hypoxemia and pulmonary hypertension in these patients. The abnormal inflammatory response and the high oxidative stress are also present at the extrapulmonary level, thus explaining the systemic character of the disorder.

[New pathophysiological concepts in pulmonary hypertension in COPD]. / Noi concepte fiziopatologice în hipertensiunea pulmonara din BPOC.

Pulmonary hypertension (PH) is a frequent complication of chronic obstructive pulmonary disease (COPD) highly correlated with the prognostic disease. In advanced stages, pulmonary vascular remodeling together with the hypoxia induced vasoconstriction represents the main factors responsible for PH. However, recent studies have demonstrated that structural anomalies of pulmonary arteries may be already evident in the initial stages of COPD, which usually lack hypoxemia. The mechanisms underlying these structural and functional alterations of pulmonary vessels are related to the deleterious effects of different components present in the cigarette smoke and to the inflammatory changes occurring in these patients. The smoking induced lesions of pulmonary arteries endothelium, either direct or secondary to the subjacent inflammation, predispose these patients to the farther action of hypoxia. Taking in account all these observations, it seems that pulmonary vascular remodeling associated to COPD follows, at least partially, a similar pathogenesis as that described within the primary PH, where the endothelial dysfunction plays the essential role.