Physical Activity and Mental Health of Patients with Pulmonary Hypertension during the COVID-19 Pandemic.

The aim of the study was to analyze the effect of personal restrictions on physical activity, mental health, stress experience, resilience, and sleep quality in patients with pulmonary hypertension (PH) during the "lockdown" period of the COVID-19 pandemic. In total, 112 PH patients and 52 age-matched healthy control subjects completed a questionnaire on the topics of physical activity, mental health, resilience, and sleep quality. PH patients had significantly lower physical activity, mental health, and sleep quality compared to age-matched healthy controls. Physical activity positively correlated with mental health and sleep quality in the PH group. Mental wellbeing and life satisfaction could be predicted by total physical activity, sleep, stress level, and resilience. PH patients appeared as an especially vulnerable group, demanding interventions to promote an active lifestyle and protect mental health in these patients. This could be helpful in counseling on how to carry out physical activity while maintaining infection control.

Anti-interleukin-5 therapy (mepolizumab) in life-threatening asthma attack: A case-based discussion.

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.

Increased frequency of the restless legs syndrome in adults with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) may suffer from iron deficiency which is a known risk factor for the restless legs syndrome (RLS), however, its prevalence has not yet been investigated in these subjects. PATIENTS AND METHODS: Adult out-patients with CF (n = 39) and healthy volunteers (n = 32) were recruited for this study. A diagnosis of RLS was made based on the diagnostic criteria established by the International Restless Legs Syndrome Study Group (IRLSSG). The IRLSSG rating scale was used to assess the severity of the disease. Furthermore, in the CF group, parameters of iron metabolism were measured in peripheral venous blood samples. RESULTS: The RLS occurred more frequently in the CF patients than the controls (n = 13/33,3% vs. n = 2/6,3%; p < 0,05). In the CF patients suffering from RLS, the mean score of the IRLSSG rating scale was 17,2 ±â€¯9,4 indicating moderate disease severity. Iron deficiency was present in the majority of the CF patients investigated (n = 33/84,6%), however, serum iron, ferritin and transferrin levels as well as transferrin saturation were similar in those with vs. without RLS. CONCLUSIONS: The frequency of the RLS is increased in adult patients with CF. On an average, its severity is moderate and it is not related to iron deficiency as evaluated by serum parameters of iron metabolism.

Intravenous treprostinil via an implantable pump in pediatric pulmonary arterial hypertension.

Intravenous prostacyclin-based therapy improves survival in children with pulmonary arterial hypertension (PAH), but is typically administered via an external infusion pump, which places a considerable burden on the patient. Implanted pumps may overcome some of the limitations of external pumps. We describe the first long-term use of an implanted pump for intravenous treprostinil delivery in a pediatric patient with PAH. Our patient was experiencing marked dyspnea on exertion despite triple combination therapy with bosentan, sildenafil, and inhaled iloprost. Parenteral prostacyclin-based therapy was discussed and the patient rejected options involving external pumps; she finally chose intravenous treprostinil delivery via an implanted pump (LENUS Pro®; fixed flow rate; 20 ml reservoir). The patient underwent pump implantation in July 2012 (aged 14 years) under general anesthesia with no peri- or postoperative complications. She showed marked improvements in fatigue and dyspnea over the subsequent weeks, and her inhaled iloprost regimen was slowly decreased and stopped after six months. During follow-up, the pump showed an unexpected, progressive increase in flow rate that allowed a treprostinil dose of 170 ng/kg/min to be achieved, but at the cost of shortened intervals between refills. The pump was therefore replaced in August 2017 with a newer model with an adjustable flow rate (Siromedes®). A catheter dislocation was corrected under local anesthesia one week after the replacement surgery. The patient is currently receiving treprostinil 170 ng/kg/min with percutaneous refills every 12-13 days. Thus, implantable pumps might be a valuable alternative to external pumps for treprostinil infusion in pediatric PAH.

Immune-regulating effects of exercise on cigarette smoke-induced inflammation.

Long-term cigarette smoking (LTCS) represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus-capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases. It is well established that exercise training exerts immune-regulating effects by activating anti-inflammatory signaling pathways. In this regard, the release of myokines from contracting skeletal muscle, the elevations of cortisol and adrenalin, the reduced expression of Toll-like receptors, and the increased mobilization of immune-regulating leukocyte subtypes might be of vital importance. Exercise training also increases the local and systemic antioxidative capacity and several compensatory mechanisms in tissues such as an increased anabolic signaling in muscle or an increased compliance of the vascular system. Accordingly, regular exercise training seems to protect long-term smokers against some important negative local and systemic consequences of smoking. Data suggest that it seems to be important to start exercise training as early as possible.

Short-term venoarterial extracorporeal membrane oxygenation for massive endobronchial hemorrhage after pulmonary endarterectomy.

OBJECTIVES: Pulmonary endarterectomy (PEA) is the only curative treatment option for patients with chronic thromboembolic pulmonary hypertension. Massive endobronchial bleeding that precludes weaning from cardiopulmonary bypass is an often-fatal complication of PEA. The aim of this study was to determine whether short-term extracorporeal membrane oxygenation (ECMO) is a safe and feasible procedure in patients with severe endobronchial bleeding. METHODS: From January 2014 to December 2016, 396 patients (mean age 60 ± 18 years, 54.5% male) underwent PEA in our department. Patients with severe endobronchial hemorrhage at the time of weaning from cardiopulmonary bypass (CPB) were switched to a heparin-coated venoarterial ECMO circuit. After full-dose protamine administration to restore normal coagulation, weaning from ECMO was attempted in the operating room. RESULTS: In-hospital mortality was 2.3% (9/396 patients). Eight patients (2.0%) developed severe endobronchial bleeding classified as diffuse (n = 6) or localized (n = 2) by bronchoscopy. After reinstitution of CPB and subsequent switch to ECMO, the mean duration of ECMO support was 49 ± 13 minutes, and all 8 patients were weaned successfully from ECMO in the operating theater without further signs of endobronchial bleeding. One patient needed venovenous ECMO support for poor oxygenation 6 hours after surgery. Seven patients were discharged after a prolonged postoperative stay of 17.6 ± 4.1 days. One patient died. This new concept significantly reduced mortality compared with previous (2009-2013) ECMO support (P = .0406). CONCLUSIONS: For patients with massive endobronchial bleeding after PEA, the intraoperative switch from CPB to venoarterial ECMO support with full-dose protamine administration is a new and potentially life-saving treatment concept.

Hemodynamic phenotyping based on exercise catheterization predicts outcome in patients with heart failure and reduced ejection fraction.

BACKGROUND: Exercise right heart catheterization (RHC) unmasks different phenotypes based on hemodynamic response to exertion in patients with heart failure. The prognostic relevance of this approach in patients with heart failure and reduced ejection fraction (HFrEF) is uncertain. METHODS: We analyzed 167 patients with HFrEF from the Kerckhoff-Klinik Heart Failure Registry who underwent supine exercise RHC with constant external workload between September 2009 and August 2014. The primary outcome was heart transplant/assist device-free survival. Hemodynamic parameters that significantly predicted outcome were identified by multivariate Cox regression analysis and assessed further by Kaplan-Meier analysis after dichotomization using cutoffs derived from receiver operating characteristic analysis. Hemodynamic phenotypes were defined based on a dichotomized flow response (exercise-induced change in cardiac output [∆CO]) combined with a dichotomized pressure response (exercise-induced change in systolic [∆sPAP] or mean pulmonary arterial pressures). RESULTS: ∆CO independently predicted transplant/assist device-free survival (multivariate hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.09-2.58; p = 0.02). Patients with ∆CO ≥1.15 liter/min had significantly better 5-year transplant/assist device-free survival than patients with lower ∆CO (72.9% vs 22.5%; log-rank p < 0.001 [Kaplan-Meier analysis]). The hemodynamic phenotype of ∆CO <1.15 liter/min combined with ∆sPAP <17.5 mm Hg was associated with worse transplant/assist device-free survival than ∆CO ≥1.15 liter/min combined with ∆sPAP ≥17.5 mm Hg (multivariate HR 7.39; 95% CI, 2.27-24.05; p = 0.001). CONCLUSIONS: Exercise RHC parameters are important prognostic indices in HFrEF. Hemodynamic phenotyping using ∆CO and ∆sPAP allows enhanced risk stratification.

The prognostic relevance of oxygen uptake in inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) present with a decreased oxygen uptake, however, the prognostic relevance of oxygen uptake (VO2 ) in inoperable CTEPH is unknown. METHODS: Patients with inoperable CTEPH were retrospectively analyzed. All patients were assessed by means of right heart catheterisation and cardio pulmonary exercise testing in semisupine position with a 30 Watt increment step-protocol. RESULTS: One-hundred and fifty-one patients (82 female (54.3%), mean age 61 ± 12.4 years) presented with a mean pulmonary arterial pressure of 40.2 ± 14.2 mmHg and pulmonary vascular resistance (PVR) of 641.9 ± 374.8 dyne∗s/cm5 . The peak VO2 (mean 13.1 ± 4.5 mL∗kg-1 ∗min-1 ) was measured at initial referral. Over a follow-up of up to 10 years (mean 4.41 ± 2.57 years), 31 patients had died. Patients with a baseline peak VO2 ≥ 10.7 mL∗kg-1 ∗min-1 [area under the receiver-operating characteristic curve (AUC) = 0.728, P = 0.001] had better survival than those with a peak VO2 ≤ 10.7 mL∗kg-1 ∗min-1 using Kaplan-Meier analysis (88.8% vs 60.1%; log rank P = 0.001). Adjusting for age, gender and PVR, multivariate analysis identified peak VO2 as a predictor of mortality [hazard ratio (HR): 2.78, 95% CI 1.01-7.63, P = 0.047]. In addition, peak VO2 failed as an independent prognostic factor in a stepwise multivariate model including all variables significant in the univariate analysis. CONCLUSIONS: In patients with inoperable CTEPH the peak VO2 is a significant predictor of survival, when adjusting for age, gender and PVR. However, peak VO2 failed as an independent prognostic factor when correcting for all significant baseline variables, which is limiting the clinical usability.

Circulating Angiopoietin-1 Is Not a Biomarker of Disease Severity or Prognosis in Pulmonary Hypertension.

BACKGROUND: Circulating angiopoietin-1 (Ang-1) has been linked to pulmonary hypertension (PH) in experimental studies. However, the clinical relevance of Ang-1 as a biomarker in PH remains unknown. We aimed to investigate the prognostic and clinical significance of Ang-1 in PH using data from the prospectively recruiting Giessen PH Registry. METHODS: Patients with suspected PH (without previous specific pulmonary arterial hypertension [PAH] therapy) who underwent initial right heart catheterization (RHC) in our national referral center between July 2003 and May 2012 and who agreed to optional biomarker analysis were included if they were diagnosed with idiopathic PAH, connective tissue disease-associated PAH (CTD-PAH), PH due to left heart disease (PH-LHD), or chronic thromboembolic PH (CTEPH), or if PH was excluded by RHC (non-PH controls). The association of Ang-1 levels with disease severity (6-minute walk distance and pulmonary hemodynamics) was assessed using linear regression, and the impact of Ang-1 levels on transplant-free survival (primary endpoint) and clinical worsening was assessed using Kaplan-Meier curves, receiver operating characteristic (ROC) analyses, and Cox regression. RESULTS: 151 patients (39, 39, 32, and 41 with idiopathic PAH, CTD-PAH, PH-LHD, and CTEPH, respectively) and 41 non-PH controls were included. Ang-1 levels showed no significant difference between groups (p = 0.8), and no significant associations with disease severity in PH subgroups (p ≥ 0.07). In Kaplan-Meier analyses, Ang-1 levels (stratified by quartile) had no significant impact on transplant-free survival (p ≥ 0.27) or clinical worsening (p ≥ 0.51) in PH subgroups. Regression models found no significant association between Ang-1 levels and outcomes (p ≥ 0.31). ROC analyses found no significant cut-off that would maximize sensitivity and specificity. CONCLUSIONS: Despite a strong pathophysiological association in experimental studies, this first comprehensive analysis of Ang-1 in PH subgroups suggests that Ang-1 is not a predictive and clinically relevant biomarker in PH.

Selexipag for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe. AREAS COVERED: We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids. EXPERT OPINION: Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side-effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials.

Heart rate response during 6-minute walking testing predicts outcome in operable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Six-minute walk test (6MWT) is routinely performed in chronic thromboembolic pulmonary hypertension (CTEPH) before pulmonary endarterectomy (PEA). However, the clinical relevance of heart rate response (ΔHR) and exercise-induced oxygen desaturation (EID) during 6MWT is remaining unknown. METHODS: Patients undergoing PEA in our center between 03/2013-04/2014 were assessed prospectively with hemodynamic and exercise parameters prior to and 1 year post-PEA. Patients with symptomatic chronic thromboembolic disease (mean pulmonary artery pressure (mPAP) <25 mmHg) and clinical relevant obstructive pulmonary disease were excluded. The following definitions were used: ΔHR = (peak HR - resting HR), percent heart rate reserve (HRR) = (peak HR -rest HR)/(220 - age - rest HR) x 100 and EID = SpO2 ≤88 %. RESULTS: Thirty-seven patients (of 116 patients screened) with mPAP of 43.2 ± 8.7 mmHg, pulmonary vascular resistance (PVR) of 605.5 ± 228.7 dyn*s/cm(5), cardiac index (CI) of 2.4 ± 0.5 l/min/m(2) and a 6MWT-distance of 404.7 ± 148.4 m and a peak VO2 of 12.3 ± 3.4 ml/min/kg prior to PEA were included. Baseline ΔHR during 6MWT was significantly associated with PVR 1 year post-PEA using linear regression analysis (r = 0.43, p = 0.01). Multivariate analysis indicated an association of HRR during 6MWT and residual PH with a hazard ratio of 1.06 (95 % Confidence interval for hazard ratio 0.99-1.14, p = 0.08). EID was observed commonly during 6MWT but no correlations to outcome parameters were found. CONCLUSIONS: This is the first prospective study to describe an association of ΔHR during 6MWT with pulmonary hemodynamics 1 year post-PEA. Our preliminary results indicate that HRR derived from 6MWT is of clinical significance. EID was commonly observed, albeit failed as a significant prognostic factor.

The Clinical Significance of HbA1c in Operable Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Glycosylated hemoglobin A1c (HbA1c) has been proposed as an independent predictor of long-term prognosis in pulmonary arterial hypertension. However, the clinical relevance of HbA1c in patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) remains unknown. The aim of the present study was to investigate the clinical significance of HbA1c as a biomarker in CTEPH. METHODS: Prospectively, 102 patients underwent pulmonary endarterectomy (PEA) in our national referral center between March 2013 and March 2014, of which after exclusion 45 patients were analyzed. HbA1c- levels, hemodynamic and exercise parameters were analyzed prior and one-year post-PEA. RESULTS: 45 patients (BMI: 27.3 ± 6.0 kg/m2; age: 62.7 ± 12.3 years) with a mean pulmonary arterial pressure (mPAP) of 43.6 ± 9.4 mmHg, a pulmonary vascular resistance (PVR) of 712.1 ± 520.4 dyn*s/cm5, a cardiac index (CI) of 2.4 ± 0.5 l/min/m2 and a mean HbA1c-level of 39.8 ± 5.6 mmol/mol were included. One-year post-PEA pulmonary hemodynamic and functional status significantly improved in our cohort. Baseline HbA1c-levels were significantly associated with CI, right atrial pressure, peak oxygen uptake and the change of 6-minute walking distance using linear regression analysis. However, using logistic regression analysis baseline HbA1c-levels were not significantly associated with residual post-PEA PH. CONCLUSIONS: This is the first prospective study to describe an association of HbA1c-levels with pulmonary hemodynamics and exercise capacity in operable CTEPH patients. Our preliminary results indicate that in these patients impaired glucose metabolism as assessed by HbA1c is of clinical significance. However, HbA1c failed as a predictor of the hemodynamic outcome one-year post-PEA.

Pulmonary Hemodynamic Response to Exercise in Chronic Thromboembolic Pulmonary Hypertension before and after Pulmonary Endarterectomy.

BACKGROUND: Pulmonary endarterectomy (PEA) is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension (CTEPH). An important predictor of outcome is postsurgical residual pulmonary hypertension. OBJECTIVE: We aimed to use the hemodynamic response during exercise before PEA as a measurement for the hemodynamic outcome 1 year after PEA. METHODS: Between January 2011 and December 2013, 299 patients underwent PEA in our center. A total of 16 patients who were assessed by means of invasive hemodynamic measurements during exercise both at baseline and 1 year after PEA were retrospectively analyzed. RESULTS: Pre-PEA mean pulmonary arterial pressure (mPAP) increased during exercise from 35.8 ± 7.6 to 53.8 ± 5.1 mm Hg, diastolic pulmonary arterial pressure (dPAP) from 21.5 ± 5.6 to 30.3 ± 9.6 mm Hg, cardiac output (CO) from 4.4 ± 0.8 to 6.5 ± 1.9 l/min and diastolic pulmonary gradient (DPG) from 14.6 ± 4.9 to 20.7 ± 12.7 mm Hg. Post-PEA mPAP increased from 23.7 ± 6.6 at rest to 43.2 ± 7.1 mm Hg, while CO increased to a higher extent from 5.1 ± 0.9 to 8.4 ± 1.9 l/min. There were significant correlations between pre-PEA DPG/CO and dPAP/CO slopes with the pulmonary vascular resistance (Spearman r = 0.578, p = 0.019, and r = 0.547, p = 0.028) and mPAP at rest after PEA (Spearman r = 0.581, p = 0.018, and r = 0.546, p = 0.028). CONCLUSIONS: In CTEPH, the presurgical dynamic DPG/CO and dPAP/CO slopes during submaximal exercise are associated with the hemodynamic outcome 1 year after PEA.

The prognostic significance of inspiratory capacity in pulmonary arterial hypertension.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) present with an altered inspiratory capacity (IC) reflecting dynamic hyperinflation (DH) that leads to mechanical constraints and excessive ventilatory demand, particularly during exercise, resulting in exertional dyspnea. OBJECTIVES: Assessment of the long-term consequences of altered IC and DH in PAH. METHODS: 50 patients with newly diagnosed PAH were prospectively recruited. All patients were assessed by means of right heart catheterization, 6-min walking distance (6MWD) test, lung function and cardiopulmonary exercise testing, including the assessment of IC. RESULTS: 37 patients with idiopathic PAH and 13 patients with conditions associated with PAH (29 female; mean age 51.6 ± 15.1 years; World Health Organization, WHO class, 2.7 ± 0.6) presented with a mean pulmonary arterial pressure of 42.8 ± 15.9 mm Hg and pulmonary vascular resistance (PVR) of 737.2 ± 592.8 dyn*s/cm(5). The mean IC at rest was 87.2 ± 17.3% pred. Kaplan-Meier analysis revealed that patients with an IC at rest >89% pred. had a significantly better 5-year survival than those with lower values (94.1 vs. 75.1%; log-rank p = 0.036). Univariate analysis identified IC at rest (% pred.) as a predictor of survival with a hazard ratio (HR) of 5.05 (95% confidence interval, CI, 0.97-26.24, p = 0.054). In multivariate analysis including PVR, WHO class, 6MWD and peak oxygen uptake as covariates, IC at rest remained an independent predictor of survival (HR: 8.06, 95% CI 0.92-70.34; p = 0.059). DH expressed as ΔIC or static hyperinflation expressed as IC/total lung capacity at rest revealed no prognostic significance. CONCLUSION: In patients with PAH, IC at rest is of prognostic significance at the time of diagnosis.