Prognosis Of Pulmonary Hypertension Research Articles

Effect of riociguat on pulmonary arterial compliance in the PATENT and CHEST studies.

Pulmonary arterial compliance is a measure of the pulsatile afterload of the right ventricle. Lower pulmonary arterial compliance is associated with reduced right ventricular function and worse prognosis in pulmonary hypertension. The effect of pulmonary vasodilators on pulmonary arterial compliance has not been evaluated in detail in pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In this post hoc analysis of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the PATENT and CHEST studies, we evaluated the change in pulmonary arterial compliance with riociguat versus placebo. Association of pulmonary arterial compliance with clinical outcomes was assessed using Kaplan–Meier and Cox proportional hazards analyses. Compared with placebo, riociguat significantly improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline was associated with survival and clinical worsening-free survival in pulmonary arterial hypertension but only with clinical worsening-free survival in chronic thromboembolic pulmonary hypertension. In patients with pulmonary arterial hypertension, pulmonary arterial compliance at follow-up ≥1.6 mL/mmHg was associated with better outcomes than pulmonary arterial compliance <1.6 mL/mmHg. In patients with chronic thromboembolic pulmonary hypertension, pulmonary arterial compliance at follow-up did not predict outcomes. Cox proportional hazards analyses showed no association between change in pulmonary arterial compliance and outcomes in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In conclusion, riociguat improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline or follow-up, rather than change in pulmonary arterial compliance, is of prognostic importance for outcomes.

Current Aspects of Definition and Diagnosis of Pulmonary Hypertension

At the 6th World Symposium on Pulmonary Hypertension (WSPH), which took place from February 27 until March 1, 2018 in Nice, scientific progress over the past 5 years in the field of pulmonary hypertension (PH) was presented by 13 working groups. The results of the discussion were published as proceedings towards the end of 2018. One of the major changes suggested by the WSPH was the lowering of the diagnostic threshold for PH from ≥ 25 to > 20 mmHg mean pulmonary arterial pressure, measured by right heart catheterization at rest. In addition, the pulmonary vascular resistance was introduced into the definition of PH, which underlines the importance of cardiac output determination at the diagnostic right heart catheterization.In this article, we discuss the rationale and possible consequences of a changed PH definition in the context of the current literature. Further, we provide a current overview on non-invasive and invasive methods for diagnosis, differential diagnosis, and prognosis of PH, including exercise tests.

Current Aspects of Definition and Diagnosis of Pulmonary Hypertension

At the 6th World Symposium on Pulmonary Hypertension (WSPH), which took place from February 27 until March 1, 2018 in Nice, scientific progress over the past 5 years in the field of pulmonary hypertension (PH) was presented by 13 working groups. The results of the discussion were published as proceedings towards the end of 2018. One of the major changes suggested by the WSPH was the lowering of the diagnostic threshold for PH from ≥ 25 to > 20 mmHg mean pulmonary arterial pressure, measured by right heart catheterization at rest. In addition, the pulmonary vascular resistance was introduced into the definition of PH, which underlines the importance of cardiac output determination at the diagnostic right heart catheterization.In this article, we discuss the rationale and possible consequences of a changed PH definition in the context of the current literature. Further, we provide a current overview on non-invasive and invasive methods for diagnosis, differential diagnosis, and prognosis of PH, including exercise tests.

Prognostic Value of Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Parameters in Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Background Cardiac right ventricular remodeling plays a substantial role in pathogenesis, progression, and prognosis of pulmonary hypertension. Cardiac magnetic resonance is considered an excellent tool for evaluation of right ventricle. However, value of right ventricular remodeling parameters derived from cardiac magnetic resonance in predicting adverse events is controversial. Methods The Pubmed (MEDLINE), Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure platform (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases were systematically searched until November 2019. Studies reporting hazard ratios (HRs) for all-cause death and composite end point of pulmonary hypertension were included. Univariate HRs were extracted from the included studies to calculate pooled HRs of each right ventricular remodeling parameter. Results Eight studies with 1120 patients examining all-cause death (female: 44%-92%, age: 40-67 years old, follow-up time: 27-48 months) and 10 studies with 604 patients examining composite end point (female: 60%-83%, age: 29-57 years old, follow-up time: 10-68 months) met the criteria. Right ventricular ejection fraction was the only parameter which could predict both all-cause death (pooled HR=0.95; P=0.014) and composite end point (pooled HR=0.95; P<0.001), although right ventricular end-diastolic volume index (pooled HR=1.01; P<0.001), right ventricular end-systolic volume index (pooled HR=1.01, P=0.045), and right ventricular mass index (pooled HR=1.03, P=0.032) only predicted composite outcome. Similar results were observed when we conducted the meta-analysis among patients with World Health Organization type I of pulmonary hypertension. Conclusions Cardiac magnetic resonance-derived right ventricular remodeling parameters have independent prognostic value for all-cause death and composite end point of patients with pulmonary hypertension. Right ventricular ejection fraction was the strongest prognostic factor among all the right ventricular remodeling parameters. Right ventricular mass index, right ventricular end-diastolic volume index, and right ventricular end-systolic volume index also demonstrated prognostic value.

Fick principle and exercise pulmonary hemodynamic determinants of the six-minute walk distance in pulmonary hypertension.

The six-minute walk test is widely used to assess the severity and prognosis of pulmonary hypertension. However, the pathophysiology underlying a compromised six-minute walk distance is incompletely characterized. The purpose of this study is to evaluate the Fick principle and pulmonary hemodynamic determinants of the six-minute walk distance in patients with suspected pulmonary hypertension. Twenty-nine patients were retrospectively studied and underwent a right heart catheterization for the evaluation of suspected pulmonary hypertension. With the pulmonary artery catheter in place, patients were moved to a treadmill and completed a six-minute walk test. Fick cardiac output and indices of right heart afterload were calculated using continuous measurements of pulmonary vascular pressures, gas exchange, and mixed venous blood samples. Fifteen subjects who walked ≤ 348 m were compared to 14 subjects who walked > 348 m. Systemic oxygen delivery was impaired in six-minute walk distance ≤ 348 m compared to six-minute walk distance > 348 m (15.2 ± 6.2 vs. 23.2 ± 6.8 mL/kg/min, p < 0.01). Impaired oxygen delivery was due to a depressed cardiac index and decreased cardiac reserve demonstrated by the change in the stroke volume index (3.0 ± 14 vs. 17 ± 15 mL/min/m2, p = 0.02). The six-minute walk distance positively correlated with oxygen delivery (r = 0.501, p = 0.006) and inversely correlated with oxygen extraction (r = 0.369, p = 0.049). A decreased six-minute walk distance was associated with an increased total pulmonary resistance (r = 0.502, p = 0.006) and pulmonary vascular resistance (r = 0.530, p = 0.003). In patients with suspected pulmonary hypertension, a decreased six-minute walk distance is due to compromised oxygen delivery, decreased cardiac reserve, and increased right ventricular afterload.

Prognostic impact of red blood cell distribution width in pulmonary hypertension patients: A systematic review and meta-analysis.

Elevated red blood cell distribution width (RDW) may correlate with a worse prognosis in pulmonary hypertension (PH), though results to date are inconsistent. The goal of this study is to detect the impact of RDW on the prognosis of PH.PubMed and EMBASE databases were searched from their inception to July 22, 2019 for relevant publications reporting the relationship between RDW and the prognosis of PH. A meta-analysis was performed, and the heterogeneity across the included studies was evaluated using I and Q statistics. We conducted sensitivity and subgroup analyses to detect sources of heterogeneity. In addition, potential publication bias was evaluated by Begg's and Egger's tests.In total, 1236 publications were retrieved, and 7 eligible publications with 666 PH patients were included in our meta-analysis. The results suggested that increased RDW can predict worse prognosis in PH (hazard ratio (HR) = 1.27, 95% confidence interval (CI) 1.11-1.45). According to subgroup analysis, study design, region, various endpoints, time of follow-up, and patient age were not sources of heterogeneity. In addition, RDW showed prognostic value in retrospective studies (HR = 1.32, 95%CI 1.15-1.51) but not in prospective studies (HR = 1.14, 95%CI 0.78-1.67). Additionally, RDW may serve as a predictive biomarker of PH in Europe (HR = 1.33, 95%CI 1.18-1.49) but not in Asia (HR = 1.20, 95%CI 0.90-1.58). Further analysis indicated that the prognostic value of RDW was influenced by patient age (>44 years: HR = 1.34, 95%CI 1.17-1.55; ≤44 years: HR = 1.20, 95%CI 0.90-1.58) and follow-up (<3 years, HR = 1.36, 95%CI 0.53-3.47; ≥3 years, HR = 1.29, 95%CI 1.14-1.45).RDW provides important prognostic information for PH patients, and this measure may be used to optimize patient management and guide clinical treatment.PROSPERO registration number: CRD42019122636.

Clinical Study on Pulmonary Hypertension Caused by Genetic Immunity and Environment

Pulmonary hypertension is a chronic pulmonary vascular disease. In recent years, quite a number of studies suggest that the increase of pulmonary artery pressure is the result of multiple factors. A better understanding of the related factors is of great significance to the prevention, diagnosis, treatment and prognosis of pulmonary hypertension. Based on this, this paper studies the genetic immunity and environmental induced pulmonary hypertension. In this paper, 60 patients with pulmonary hypertension in our hospital from January 2020 to the first half of July 2020 were selected as the research objects. According to the pathogenic factors, the patients were divided into groups. Among them, pulmonary hypertension caused by genetic factors was group A, and pulmonary hypertension caused by environmental factors was group B. This study found that the incidence rate of family genetic history reached 6%, and the proportion of diseases caused by immune factors accounted for 2%. Because of the high altitude hypoxia environment, about 5% accounted for 5%. Smoking is the main factor leading to the morbidity of pulmonary hypertension, accounting for up to 70%. The results of this study provide theoretical basis for the treatment of pulmonary hypertension caused by genetic immunity and environment.

Right heart failure in pulmonary hypertension: Diagnosis and new perspectives on vascular and direct right ventricular treatment.

Adaptation of right ventricular (RV) function to increased afterload-known as RV-arterial coupling-is a key determinant of prognosis in pulmonary hypertension. However, measurement of RV-arterial coupling is a complex, invasive process involving analysis of the RV pressure-volume relationship during preload reduction over multiple cardiac cycles. Simplified methods have therefore been proposed, including echocardiographic and cardiac MRI approaches. This review describes the available methods for assessment of RV function and RV-arterial coupling and the effects of pharmacotherapy on these variables. Overall, pharmacotherapies for pulmonary hypertension have shown beneficial effects on various measures of RV function, but it is often unclear if these are direct RV effects or indirect results of afterload reduction. Studies of the effects of pharmacotherapies on RV-arterial coupling are limited and mostly restricted to experimental models. Simplified methods to assess RV-arterial coupling should be validated and incorporated into routine clinical follow-up and future clinical trials. 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.

Healthcare utilization, medical expenditure, and mortality in Korean patients with pulmonary hypertension

BackgroundLimited data exists regarding healthcare utilization, medical expenses, and prognosis of pulmonary hypertension (PH) according to the World Health Organization (WHO) classification. We aimed to investigate mortality risk, healthcare utilization and medical expenditure in patients with PH across the five diagnostic subgroups.MethodsWe identified 2185 patients with PH, defined as peak tricuspid regurgitation velocity > 3.4 m/sec, among the consecutive patients referred for echocardiography between 2009 and 2015. Using diagnostic codes, medical records, and echocardiographic findings, the enrolled patients were classified according to the five subgroups by WHO classification. Healthcare utilization, costs, and all-cause mortality were assessed.ResultsDiagnostic subgroups of PH demonstrated significantly different clinical features. During a median of 32.4 months (interquartile range, 16.2–57.8), 749 patients (34.3%) died. Mortality risk was the lowest in group II (left heart disease) and highest in group III (chronic lung disease). The etiologies of pulmonary arterial hypertension (PAH) had significant influence on the mortality risk in group I, showing the worst prognosis in PAH associated with connective tissue disease. Medical expenditure and healthcare utilization were different between the PH subgroups: groups II and V had more hospitalizations and medical expenses than other groups. Regardless of PH subgroups, the severity of PH was associated with higher mortality risk, more healthcare utilization and medical expenditure.ConclusionsSignificant differences in clinical features and prognostic profiles between PH subgroups reflect the differences in pathophysiology and clinical consequences. Our findings highlight the importance of comprehensive understanding of PH according to the etiology and its severity.

Echocardiographic estimation of right ventricular wall tension: haemodynamic comparison and long-term follow-up.

Prognosis in pulmonary hypertension is strictly linked to right ventricle failure, which results from uncoupling between right ventricle function and its afterload. This study sought to describe how to estimate with echocardiography right ventricular wall tension, its correlation with right ventricle haemodynamics and its prognostic role. A total of 190 patients without overt right ventricle failure but with suspected pulmonary hypertension on a previous echocardiogram underwent right heart catheterization and nearly-simultaneous echocardiography. Right ventricular wall tension was estimated according to Laplace’s law as right ventricle length × tricuspid regurgitation peak gradient and it was correlated with right ventricle haemodynamic profile; its potential prognostic impact was tested along with canonical right ventricle function parameters. Right ventricular wall tension correlated significantly with invasive estimation of right ventricle end-diastolic pressure (R: 0.343, p < 0.001) and with several other haemodynamic variables, such as mean pulmonary artery pressure, pulmonary artery compliance, transpulmonary gradient, pulmonary vascular resistance, right atrial pressure and right ventricle stroke work index (all p < 0.001). At a mean follow-up of five years and three months, only right ventricular wall tension was associated to all-cause mortality (p = 0.036), while tricuspid annular plane systolic excursion (p = 0.536), right ventricle fractional area change (p = 0.383), right ventricle fractional area change (p = 0.076), tricuspid regurgitation peak gradient (p = 0.107) and tricuspid annular plane systolic excursion/tricuspid regurgitation peak gradient (p = 0.181) could not. We identified a novel bedside echocardiographic predictor of altered right ventricle haemodynamics, which is precociously altered in patients without overt right ventricle failure and is associated to all-cause mortality at a long-term follow-up. Further studies are needed to confirm its role in pulmonary hypertension patients.

Dynamic right ventricular-pulmonary arterial uncoupling during maximum incremental exercise in exercise pulmonary hypertension and pulmonary arterial hypertension.

Despite recent advances, the prognosis of pulmonary hypertension (PH) remains poor. While the initial insult in PH implicates the pulmonary vasculature, the functional state, exercise capacity, and survival of such patients are closely linked to right ventricular (RV) function. In the current study, we sought to investigate the effects of maximum incremental exercise on the matching of RV contractility and afterload (i.e. right ventricular–pulmonary arterial [RV–PA] coupling) in patients with exercise PH (ePH) and pulmonary arterial hypertension (PAH). End-systolic elastance (Ees), pulmonary arterial elastance (Ea), and RV–PA coupling (Ees/Ea) were determined using single-beat pressure-volume loop analysis in 40 patients that underwent maximum invasive cardiopulmonary exercise testing. Eleven patients had ePH, nine had PAH, and 20 were age-matched controls. During exercise, the impaired exertional contractile reserve in PAH was associated with blunted stroke volume index (SVI) augmentation and reduced peak oxygen consumption (peak VO2 %predicted). Compared to PAH, ePH demonstrated increased RV contractility in response to increasing RV afterload during exercise; however, this was insufficient and resulted in reduced peak RV–PA coupling. The dynamic RV–PA uncoupling in ePH was associated with similarly blunted SVI augmentation and peak VO2 as PAH. In conclusion, dynamic rest-to-peak exercise RV–PA uncoupling during maximum exercise blunts SV increase and reduces exercise capacity in exercise PH and PAH. In ePH, the insufficient increase in RV contractility to compensate for increasing RV afterload during maximum exercise leads to deterioration of RV–PA coupling. These data provide evidence that even in the early stages of PH, RV function is compromised.

Right ventricular function inpulmonary (arterial) hypertension.

The right ventricle (RV) is the main determinant of prognosis in pulmonary hypertension. Adaptation and maladaptation of the RV are of crucial importance. In the course of disease, RV contractility increases through changes in muscle properties and muscle hypertrophy. At acertain point, the point of "uncoupling," the afterload exceeds contractility, and maladaptation as well as dilation occurs to maintain stroke volume (SV). To understand the adaptational processes and to further develop targeted medication directly affecting load-independent contractility, an accurate and precise assessment of contractility and RV-pulmonary artery (PA) coupling should be performed. In this review, we shed light on existing methods to assess RV function, including the gold standard measurement of contractility and RV-PA coupling, and we evaluate existing surrogates of RV-PA coupling.

Analysis of the Severity and Prognosis of Pulmonary Hypertension Associated With Bronchiectasis.

Analysis of the Severity and Prognosis of Pulmonary Hypertension Associated With Bronchiectasis.

CMR Right Ventricular-Pulmonary Arterial Coupling and Right Ventricular Trabecular Complexity: Prognostic in Lung Transplant Assessment?

Purpose Right ventricular (RV) function influences prognosis in pulmonary hypertension (PH), but key metrics are not clear. We assessed a cardiac magnetic resonance (CMR) index of RV-pulmonary arterial (PA) coupling as well as right ventricular (RV) trabecular complexity by its fractal dimension (FD), correlating to imaging indices and outcome. Methods Patients underwent CMR to assess biventricular volumes and systolic function. RV FD was assessed on CMR using custom-written code (FracAnalyse). RV-PA coupling was estimated by stroke volume (SV)/ RV end-systolic volume (ESV) ratio. Correlation between variables was assessed with the Pearson correlation test. Survival was analysed using the Cox proportional hazard ratio with the primary outcome of time to death. Results 78 patients were assessed for lung transplantation between 2013-2018, with a median follow up of 18.33 (interquartile range 17.25) months. 93% of the patients had underlying lung disease. 48 out of 62 patients had echo-detected PH (RV systolic pressure of > 35mmHg). Both SV/ESV and RV FD correlated to mean PA pressure (mPAP), RV ejection fraction (EF), indexed RV end-diastolic volumes (RVEDVi) and ESV (RVESVi), and right atrial (RA) area. On univariate analysis, survival was predicted by SV/ESV, RVEF, RVEDVi and RVESVi. Conclusion RV functional adaptation to afterload assessed by CMR predicts survival in patients referred for lung transplant assessment, on univariate analysis. Fractal analysis of RV trabecular complexity correlated with metrics influencing RV remodelling and contractility, but not survival.

Soluble neprilysin does not correlate with prognosis in pulmonary hypertension.

AimsIt has been reported that circulating soluble neprilysin (sNEP), which catalyses the degradation of several vasodilator peptides such as natriuretic peptides, predicts prognosis in heart failure patients with reduced ejection fraction. Hypoxia‐induced decrease in NEP expression in lungs has been reported. However, the associations between sNEP and haemodynamic parameters, as well as the prognostic impact of sNEP in pulmonary hypertension (PH), remain unclear. We aimed to clarify the relationships between sNEP and natriuretic peptide, haemodynamics (e.g. parameters of echocardiography and right heart catheter) or prognosis in PH patients.Methods and resultsFirst, we examined the associations between sNEP levels and natriuretic peptide, echocardiography, or right heart catheter in PH patients (mean pulmonary artery pressure ≥ 25 mmHg and pulmonary artery wedge pressure ≤ 15 mm Hg on the basis of right heart catheterization, n = 79). Next, we followed up the patients for all‐cause mortality. Laboratory data revealed no significant correlations between sNEP and B‐type natriuretic peptide (R = 0.022, P = 0.872), N‐terminal proBNP (R = −0.018, P = 0.872), and high‐sensitivity troponin I (R = 0.206, P = 0.107). Regarding the parameters of echocardiography and right heart catheter, there were no significant correlations between sNEP and left ventricular ejection fraction (R = −0.036, P = 0.764), right ventricular fractional area change (R = −0.259, P = 0.064), tricuspid valve pressure gradient (R = −0.037, P = 0.767), and any of the right heart catheter parameters. In the Kaplan–Meier analysis (mean follow‐up, 1284 days, log‐rank P = 0.531), all‐cause mortality rates were comparable between the higher NEP group (sNEP ≥ median levels of 1.45 ng/mL, n = 39) and the lower NEP group (sNEP < 1.45 ng/mL, n = 40). In the Cox proportional hazard analysis, sNEP was not a predictor of all‐cause mortality (hazard ratio 0.902, 95% CI 0.674–1.207, P = 0.487) in PH patients.ConclusionsCirculating sNEP does not correlate with natriuretic peptide, haemodynamic parameters, or prognosis in patients with PH.

Transthoracic echocardiography: a surrogate tool for predicting pulmonary hypertension using pulmonary artery to aorta ratio

Background Owing to the nonspecific and subtle nature of physical signs and symptoms of pulmonary hypertension (PH) in early stages, treatment is usually delayed despite advancement over the past decade. Use of transthoracic echocardiography (TTE) as the initial noninvasive modality in the screening and evaluation of PH can provide key information about the etiology and the prognosis of PH, thereby avoiding the complications associated with the invasive methods. The aim of this study was to determine the usefulness of main pulmonary artery (mPA) and ascending aorta (AscAo) ratio using TTE. Patients and methods In this prospective observational study, 30 adult patients undergoing elective coronary artery bypass grafting surgery were enrolled. Postanesthetic induction mPA and AscAo transverse diameters were measured using TTE. The mean pulmonary arterial pressures (mPAPs) were recorded using a direct pulmonary artery puncture after sternotomy. Correlations were established using the Pearson correlation coefficient. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results mPA : AscAo ratio demonstrated significant linear correlation with mPAP (i.e. r=0.553, P=0.00152). Sensitivity, specificity, positive predictive value, negative predictive value were 80, 100, 80, and 100%, respectively, for an mPAP of up to 25 mmHg. Conclusion TTE-guided measurement of mPA : AscAo ratio can be used as a simple and easily reproducible noninvasive method in predicting PH not only in cardiac but also in other noncardiac settings.

Association of hyperuricemia and pulmonary hypertension: A systematic review and meta-analysis

Objectives: To investigate the association of hyperuricemia with pulmonary hypertension (PH) in term of subsequent development, severity, and prognosis of PH.Methods: The authors systematically reviewed articles from databases and conducted meta-analyses as follows: (1) association of serum uric acid (UA) levels with the presence of PH; (2) association between serum UA levels and subsequent development of PH, in terms of odds ratio of the development of PH; and (3) association of serum UA levels with severity and prognosis of PH, in terms of pulmonary arterial pressure and hazard ratio of death.Results: Twenty-six studies published between 1999 and 2017 were included. The level of serum UA was higher in subjects with PH than subjects without PH and this finding was observed regardless of status of diuretics use or renal function. The odds ratio of the development of PH was 2.32 (95% CI, 1.05–5.15) in subjects with hyperuricemia. Pulmonary arterial pressure among subjects with PH was also higher in subjects with hyperuricemia than subjects with normouricemia. There was a 19% increased hazard ratio of death (95% CI, 1.06–1.33) among patients with PH who had hyperuricemia.Conclusion: Hyperuricemia is associated with the subsequent development, worse severity and poor prognosis of PH.

MiR-190a-5p participates in the regulation of hypoxia-induced pulmonary hypertension by targeting KLF15 and can serve as a biomarker of diagnosis and prognosis in chronic obstructive pulmonary disease complicated with pulmonary hypertension.

PurposemiR-190a-5p expression alters dynamically in response to hypoxia. However, the role of miR-190a-5p expression in hypoxia-induced pulmonary hypertension (PH) remains unclear. We sought to correlate the miR-190a-5p expression levels with the severity, diagnosis, and prognosis of PH in relation to chronic obstructive pulmonary disease (COPD-PH). Additionally, we evaluated the effect of miR-190a-5p through in vitro experiments on human pulmonary endothelial cells (HPECs) that were exposed to hypoxia and in vivo experiments using an animal model of hypoxia-induced PH.MethodsCirculating miR-190a-5p levels were measured from 73 patients with PH and 32 healthy controls through quantitative real-time PCR. The levels of miR-190a-5p and the expression of Krüppel-like factor 15 (KLF15) were analyzed in HPECs that were exposed to hypoxia, and the effects of antagomir-190a-5p in mice with chronic hypoxia-induced PH were tested. Target gene analysis was performed by Western blot and luciferase assay.ResultsThe miR-190a-5p level was significantly higher in patients with COPD-PH than in the healthy controls. Higher miR-190a-5p levels were associated with a greater severity of COPD-PH. In vitro experiments on HPECs showed that exposure to hypoxia increased the miR-190a-5p levels significantly. KLF15 was validated as a target of miR-190a-5p. Transfection with miR-190a-5p mimicked inhibition of KLF15 expression in HPECs. In the mouse model of PH, antagomir-190a-5p reduced right ventricular systolic pressure and enhanced the KLF15 expression levels in lung tissue.ConclusionmiR-190a-5p regulates hypoxia-induced PH by targeting KLF15. The circulating levels of miR-190a-5p correlate with the severity of COPD-PH, thereby confirming the diagnostic and prognostic value of this parameter in COPD-PH.

Sexually Dimorphic Regulation of EET Synthesis and Metabolism: Roles of Estrogen.

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenase and are hydrolyzed by soluble epoxide hydrolase (sEH). Circulating and tissue levels of EETs are controlled by CYP (EET synthesis) and sEH (EET degradation). Therefore, both increases in CYP activity and decreases in sEH expression potentiate EET bioavailability, responses that prevail in the female sex as a function of estrogen. This mini review, based on subtitles listed, briefly summarizes studies focusing specifically on (1) female-specific potentiation of CYP/epoxygenase activity to compensate for the endothelial dysfunction; and (2) estrogen-dependent downregulation of sEH expression, which yields divergent actions in both systemic and pulmonary circulation, respectively.Estrogen-Potentiating EET Synthesis in Response to Endothelial Dysfunction: This section summarizes the current understanding regarding the roles of estrogen in facilitating EET synthesis in response to endothelial dysfunction. In this regard, estrogen recruitment of EET-driven signaling serves as a back-up mechanism, which compensates for NO deficiency to preserve endothelium-dependent vasodilator responses and maintain normal blood pressure.Estrogen-Dependent Downregulation of Ephx2/sEH Expression: This section focuses on molecular mechanisms responsible for the female-specific downregulation of sEH expression.Roles of EETs in Systemic Circulation, as a Function of Estrogen-Dependent Downregulation of sEH: This section summarizes studies conducted on animals that are either deficient in the Ephx2 gene (sEH-KO) or have been treated with sEH inhibitors (sEHIs), and exhibit EET-mediated cardiovascular protections in the cerebral, coronary, skeletal, and splanchnic circulations. In particular, the estrogen-inherent silencing of the Ephx2 gene duplicates the action of sEH deficiency, yielding comparable adaptations in attenuated myogenic vasoconstriction, enhanced shear stress-induced vasodilation, and improved cardiac contractility among female WT mice, male sEH-KO and sEHI-treated mice.Roles of Estrogen-Driven EET Production in Pulmonary Circulation: This section reviews epidemiological and clinical studies that provide the correlation between the polymorphism, or mutation of gene(s) involving estrogen metabolism and female predisposition to pulmonary hypertension, and specifically addresses an intrinsic causation between the estrogen-dependent downregulation of Ephx2 gene/sEH expression and female-susceptibility of being pulmonary hypertensive, a topic that has never been explored before. Additionally, the issue of the “estrogen paradox” in the incidence and prognosis of pulmonary hypertension is discussed.

Impact of comorbidities and delay in diagnosis in elderly patients with pulmonary hypertension.

Patient age at diagnosis of pulmonary hypertension is steadily increasing. The present study sought to analyse clinical characteristics, time to diagnosis and prognosis of pulmonary hypertension in elderly and very elderly patients.A study was conducted in a French regional referral centre for pulmonary hypertension. All consecutive patients diagnosed with pre-capillary pulmonary hypertension were included and categorised according to age: <65 years (“young”), 65–74 years (“elderly”) and ≥75 years (“very elderly”).Over a 4-year period, 248 patients were included: 101 (40.7%) were young, 82 (33.1%) were elderly and 65 (26.2%) were very elderly. The median age at diagnosis among the total population was 68 years. Compared with young patients, elderly and very elderly patients had a longer time to diagnosis (7±48, 9±21 and 16±32 months, respectively; p<0.001). Patients ≥75 years also more often had group 4 pulmonary hypertension. The median overall survival was 46±1.4 months, but was only 37±4.9 months in elderly patients and 28±4.7 months in very elderly patients. Survival from the first symptoms and survival adjusted to comorbidity was similar across age groups.Patient age should be taken into account when diagnosing pulmonary hypertension as it is associated with a specific clinical profile and a worse prognosis. The difference in prognosis is likely to be related to a delay in diagnosis and a greater number of comorbidities.