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Background: The ratios of tricuspid annular plane systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (PASP), fractional area change/invasively measured mean pulmonary artery pressure, right ventricular (RV) area change/end-systolic area, TAPSE/pulmonary artery acceleration time, and stroke volume/end-systolic area have been proposed as surrogates of RV-arterial coupling. The relationship of these surrogates with the gold standard measure of RV-arterial coupling (invasive pressure-volume loop-derived end-systolic/arterial elastance [Ees/Ea] ratio) and RV diastolic stiffness (end-diastolic elastance) in pulmonary hypertension remains incompletely understood. We evaluated the relationship of these surrogates with invasive pressure-volume loop-derived Ees/Ea and end-diastolic elastance in pulmonary hypertension. Methods: We performed right heart echocardiography and cardiac magnetic resonance imaging 1 day before invasive measurement of pulmonary hemodynamics and single-beat RV pressure-volume loops in 52 patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. The relationships of the proposed surrogates with Ees/Ea and end-diastolic elastance were evaluated by Spearman correlation, multivariate logistic regression, and receiver operating characteristic analyses. Associations with prognosis were evaluated by Kaplan-Meier analysis. Results: TAPSE/PASP, fractional area change/mean pulmonary artery pressure, RV area change/end-systolic area, and stroke volume/end-systolic area but not TAPSE/pulmonary artery acceleration time were correlated with Ees/Ea and end-diastolic elastance. Of the surrogates, only TAPSE/PASP emerged as an independent predictor of Ees/Ea (multivariate odds ratio: 18.6; 95% CI, 0.8–96.1; P =0.08). In receiver operating characteristic analysis, a TAPSE/PASP cutoff of 0.31 mm/mm Hg (sensitivity: 87.5% and specificity: 75.9%) discriminated RV-arterial uncoupling (Ees/Ea Conclusions: Echocardiographically determined TAPSE/PASP is a straightforward noninvasive measure of RV-arterial coupling and is affected by RV diastolic stiffness in severe pulmonary hypertension. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03403868.

The Breelib™ nebulizer was designed to reduce iloprost inhalation times for patients with pulmonary arterial hypertension (PAH). In 30 patients with PAH, rapid inhalation of iloprost 2.5 µg using Breelib™ caused significant improvements in invasively measured afterload and cardiac index but not echocardiographic right ventricular strain during 30 min post-inhalation.

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.

Cardiopulmonary exercise testing (CPET) is an important tool for assessing functional capacity and prognosis in pulmonary arterial hypertension (PAH). However, the associations of CPET parameters with the adaptation of right ventricular (RV) function to afterload remain incompletely understood.In this study, 37 patients with PAH (idiopathic in 31 cases) underwent single-beat pressure–volume loop measurements of RV end-systolic elastance (Ees), arterial elastance (Ea) and diastolic elastance (Eed). Pulmonary arterial stiffness was assessed by magnetic resonance imaging. The results were correlated to CPET variables. The predictive relevance of RV function parameters for clinically relevant ventilatory inefficiency, defined as minute ventilation/carbon dioxide production (V′E/V′CO2) slope >48, was evaluated using logistic regression analysis.The median (interquartile range) of the V′E/V′CO2 slope was 42 (32–52) and the V′E/V′CO2 nadir was 40 (31–44). The mean±sd of peak end-tidal carbon dioxide tension (PETCO2) was 23±8 mmHg. Ea, Eed and parameters reflecting pulmonary arterial stiffness (capacitance and distensibility) correlated with the V′E/V′CO2 slope, V′E/V′CO2 nadir, PETCO2 and peak oxygen pulse. RV Ees and RV–arterial coupling as assessed by the Ees/Ea ratio showed no correlations with CPET parameters. Ea (univariate OR 7.28, 95% CI 1.20–44.04) and Eed (univariate OR 2.21, 95% CI 0.93–5.26) were significantly associated with ventilatory inefficiency (pOur data suggest that impaired RV lusitropy and increased afterload are associated with ventilatory inefficiency in PAH.

Utilising biomarkers to predict right heart maladaptive phenotype: a step toward precision medicinehttps://bit.ly/35N5czX

A Streptococcus suis isolate from a German hunter with streptococcal toxic shock-like syndrome (STSLS) and four additional zoonotic isolates were genotyped as mrp + epf * (variant 1890) sly + cps2 + . All five zoonotic German strains were characterized by high multiplication in human blood samples ex vivo , but induction of only low levels of proinflammatory cytokines compared to a Chinese STSLS strain.

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p−1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (pCILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

Right ventricular ejection fraction can be calculated from a pressure curvehttp://bit.ly/2tjE37Q

Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH. CA extern

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO–cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients.

B: Pulmonary hypertension (PH) is often diagnosed in an advanced state. Partial pressure of end tidal Carbon dioxide (PETCO2) has been previously identified as a meaningful parameter in pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the diagnostic relevance of PETCO2 in various forms of PH is unknown. Therefore, the EARLIER study was designed to analyze the diagnostic accuracy of PETCO2. M+R: The study compromises of 2 parts. A retrospective analysis of all patients referred for diagnostic right heart catheter to our referral center between 2000 and 2016. Patients were included if cardiopulmonary exercise testing with measurement of resting PETCO2 at the time of initial RHC was available. In total 1338 patients were analyzed. The following etiologies (according to the current clinical classification) were confirmed: Nice class I=241, II=362, III=198, IV= 235, invasive exclusion of PH 302. The area under the curve to diagnose PH class I or IV was 0.703. The second part: a prospective validation of the PETCO2 cut-off in an out-patient setting is ongoing. C: The first part of the EARLIR study confirmed the diagnostic potential of PETCO2 in PAH and CTEPH patients. If PETCO2 will prove its robustness in an out-patient setting will be explored within the ongoing prospective part. fig1: sensitivity (red) and specificity (blue) to detect PAH and CTEPH.

Background: This study aims to investigate the acute hemodynamic effects of a single inhalation of Iloprost during right heart catheterization using the Breelib nebulizer. Methods: Prospectively, we analyzed the acute hemodynamic response in patients with PAH (n=15) between May and December 2017. All patients gave written informed consent and the study was approved by the local ethic committee. The acute hemodynamic response of a single inhalation of Iloprost with 2.5μg was followed over 30minutes. Change of pulmonary hemodynamics and adverse events were assessed at baseline and 5, 10, 15, 30minutes. Hemodynamic parameters at baseline and over time were analyzed with paired-t-test or Wilcoxon Signed Rank test, as appropriate, with p Results: Patients presented with a median pulmonary vascular resistance(PVR) of 488 IQR [400-1086]dyne*s/cm5 and a mean cardiac index(CI) of 2.7 ± 0.7l/min/m2 at baseline. After inhalation PVR significantly decreased (PVR 5min: 359 [292-903]dyne*s/cm5, p =0.001) and CI significantly increased (CI 5min: 3.1±0.9l/min/m2, p=0.002). 10 min after inhalation this characteristic pattern was still observed (PVR 10min: 409[313-976]dyne*s/cm5, p = 0.001; CI 10min: 3.1±0.9, p =0.005). Even 30min after inhalation PVR was lower and CI was enhanced in comparison with baseline (PVR 30min: 410[379-1149]dyne*s/cm5, p=0.053; CI 30min: 2.9±0.8l/min/m2, p=0.022). No adverse events were observed. Conclusions: Iloprost inhalation with 2.5μg via the Breelib nebulizer showed a strong acute hemodynamic effect on the pulmonary circulation with a substantial decrease in PVR.

Background: The soluble guanylate cyclase stimulator riociguat has been approved for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, its acute effect on the pulmonary circulation within a real-world setting is unknown. Methods: Prospectively, we analyzed the acute response in patients with PAH (n=15) and CTEPH (n=26) between 04/2016-08/2017. All patients gave written informed consent. Invasive hemodynamics were obtained at baseline and after administration of 1mg oral Riociguat every 15 min, until 90 min. Hemodynamic parameters at baseline and 90 min were analyzed with paired-t-test or Wilcoxon Signed Rank test, with p Results: The majority of patients were therapy-naive (88%). In comparison with baseline mPAP remained unchanged (p=0.64), PVR decreased (relative change -7.8± 15.6%, p= 0.07) and CI increased (relative change 5.6± 13.9%, p= 0.3) at 90min, albeit not-significant in PAH. In CTEPH mPAP remained unchanged (p=0.74), PVR substantially decreased (relative change -12.4± 20%, p= 0.001) and CI significantly increased (relative change 12.9± 14.9%, p Conclusions: Within a real world setting acute effects of oraly administered riociguat could be demonstrated for CTEPH and partly for PAH patients. Further explorations with a larger sample size are warranted to elucidate acute responder and non-responder.

B: Patients with pulmonary hypertension (PH) on stable background therapy are often able to live a life with only few restrictions. Quality of life includes flights for many people. But the hypobaric hypoxia present during high altitude can have major impact on the medical condition of these patients. Evidence is lacking and the recommendations in the current guidelines are derived from other chronic lung disease. We aim to fill this gap of knowledge. M+R: PEGASUS is a prospective, multicenter, multinational observational study which started in 2017 and is open until 2019. Primary endpoint is the safety of commercial air travel for patients with PH. In addition, adverse events will be associated with clinical parameters before flight to detect possible risk factors. Up to February 2018, 200 patients were prospectively included and 22 flights were documented. No adverse event with the need for medical intervention occurred so far. The flying participants had a pulmonary vascular resistance of 5.6 Wood units (median, interquartile range(IQR) 1.8), oxygen saturation at the end of six-minute-walking-test was 93% (IQR 7). 35% use oxygen at home. 7 of the 22 flying patients had a desaturation during flight below 91% measured by pulsoxymeter, three below 86%. 8 patients did not use oxygen while on the airplane and had more severe desaturations down to 78% while the minimum oxygen saturation was 88% in patients using oxygen on board. C: We are expecting important safety data for PH patients who travel by plane. Every PH patient is cordially invited to register before flying: pegasus.studie@gmx.de

The ratio of tricuspid annular plane systolic excursion to systolic pulmonary artery pressure is a simple echocardiographic parameter that reflects haemodynamic severity and predicts survival in pulmonary hypertension due to lung diseases.http://bit.ly/2KgLAbR

We report about a case of a compassionate off-label use of the anti-interleukin-5-agent mepolizumab in a ventilated patient with life-threatening asthma attack in eosinophilic asthma. The patient suffered from severe eosinophilic asthma and was transmitted to our hospital with an asthma attack and a life-threatening respiratory state under ventilation. Since high dose steroids had not yielded a sufficient respiratory improvement mepolizumab was administered subcutaneously. After administration of mepolizumab respiratory state and ventilation parameter improved significantly. Two days after administration the patient was weaned could be extubated 8 days later and recovered completely from the asthma attack.The presented clinical case is suggestive of future clinical trials or registry studies to evaluate potential clinical benefits of anti-interleukin-5 treatment in patients with severe exacerbations of eosinophilic asthma. Keywords: Anti-IL-5-therapy, Asthma, Eosinophilia, Exacerbation, Intensive care medicine

Background Thyroid disease is common in patients with pulmonary hypertension (PH), but its effect on long-term survival remains unknown. We examined the prognostic significance of thyroid hormone levels of free triiodothyronine (fT3) and free thyroxine and thyroid-stimulating hormone (TSH), and thyroid hormone replacement (THR) therapy in PH. Methods We conducted a retrospective analysis of 1,756 patients enrolled in the Giessen PH Registry in 1999 to 2013 with baseline thyroid function data; of these, 355, 533, 498, and 370 had pulmonary arterial hypertension (PAH); including 192 with idiopathic PAH (iPAH), PH due to left heart disease, PH due to lung diseases, and chronic thromboembolic PH (CTEPH), respectively. Thyroid function parameters associated with mortality were identified using Cox regression and Kaplan-Meier analyses. Results Transplant-free survival at 1, 3, and 5 years was 86.7%, 65.6%, and 53.0%, respectively. Absence of THR therapy was an independent predictor of death in iPAH (multivariate hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06–5.75). In patients without THR therapy, TSH levels in the lowest and highest quartiles (compared with the middle 2 quartiles) independently predicted death in iPAH (HR, 1.98; 95% CI, 1.07–3.67), whereas reduced fT3 levels were independently associated with increased death in PAH (HR, 8.30; 95% CI, 2.50–25.00) and CTEPH (HR, 1.79; 95% CI, 1.14–4.20). Conclusions Thyroid hormone levels and THR therapy are prognostic factors in iPAH, PAH, and CTEPH. Prospective studies are warranted to verify the prognostic significance of thyroid function and the effect of THR therapy in PH.

This study aimed to reveal the pathophysiological signalling responsible for radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis. IkappaB was upregulated in irradiated hepatocytes. Administration of IkappaB antisense oligonucleotides prior to irradiation inhibited occurrence of apoptosis after TNF-alpha administration. Caspases-8, -9 and -3 activities were increased in irradiated hepatocytes and downregulation of apoptosis by IkappaB antisense oligonucleotides was mediated by suppression of caspases-9 and -3 activation but not of caspase-8 activation, suggesting that radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis additionally requires changes upstream of caspase-8 activation. Herein, upregulation of FLIP may play a crucial role. Cleavage of bid, upregulation of bax, downregulation of bcl-2 and release of cytochrome c after TNF-alpha-administration depend on radiation-induced upregulation of IkappaB, thus demonstrating an apoptosis permitting effect of IkappaB.