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Abstract Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP − end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH. Trial registration. NCT04663217.

Background Cancer is one of the leading causes of death worldwide, and cardiopulmonary comorbidities may further adversely affect cancer prognosis. We recently described lung cancer-associated pulmonary hypertension (PH) as a new form of PH and comorbidity of lung cancer. While patients with lung cancer with PH had significantly reduced overall survival compared with patients without PH, the prevalence and impact of PH in other cancers remain unclear.Methods In this retrospective, observational cohort study, we analysed the prevalence and impact of PH on clinical outcomes in 1184 patients with solid tumours other than lung cancer, that is, colorectal, head and neck, urological, breast or central nervous system tumours, using surrogate markers for PH determined by CT.Results PH prevalence in this cohort was 10.98%. A Cox proportional hazard model revealed a significant reduction in the median survival time of patients with cancer with PH (837 vs 2074 days; p

IntroductionEndobronchial foreign body aspiration is not common in adults, but it is a life-threatening event. Recurrent pneumonias by chronic retention of foreign body often lead to initial medical presentation of the patient. However, lymphoplasmacellular bronchitis with adenomatous hyperplasia and squamous epithelium metaplasia with complete or partial blockage of lobar bronchus mimicking lung tumor is rare in literature, and this particular condition is often misdiagnosed.Case presentationwe report our experience in the diagnostic and management of two elderly patients with recurrent pneumonia, admitted in hospital for further examination. In both patients, with no history of aspiration, the cherry pit was detected during bronchoscopy and recanalization with flexible cryoprobe, surrounded by purulent secretion, occluding completely the right upper lobe in the first case, and partially the left lower lobe associated with persistent actinomycosis in the second case, with signs of local inflammation, bronchial adenomatous hyperplasia mimicking lung tumor at initial bronchoscopic examination. Histology showed a lymphoplasmacellullar bronchitis with adenomatous hyperplasia and squamous epithelium metaplasia because of chronic retention of foreign body.ConclusionBronchoscopy examination should be considered in cases where there is an unresolved chronic cough with recurrent pneumonia or persistent actinomycosis in patients with high risk. Cryoprobe is a safe and feasible approach for treatment of airway obstructions due to chronic foreign body retention. Furthermore, relevant findings are discussed here, along with a review of the pathologic alterations and treatment modalities seen in chronic retention of foreign body and airway injury.

Abstract Aims Commercially available integrated software for echocardiographic measurement of stroke work (SW) is increasingly used for the right ventricle, despite a lack of validation. We sought to assess the validity of this method [echo‐based myocardial work (MW) module] vs. gold‐standard invasive right ventricular (RV) pressure–volume (PV) loops. Methods and results From the prospectively recruiting EXERTION study (NCT04663217), we included 42 patients [34 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and 8 patients with absence of cardiopulmonary disease] with RV echocardiography and invasive PV catheterization. Echocardiographic SW was assessed as RV global work index (RVGWI) generated via the integrated pressure–strain MW software. Invasive SW was calculated as the area bounded by the PV loop. An additional parameter derived from the MW module, RV global wasted work (RVGWW), was correlated with PV loop measures. RVGWI significantly correlated with invasive PV loop‐derived RV SW in the overall cohort [rho = 0.546 (P

BackgroundNucleated red blood cells (nRBC) are precursor cells of the erythropoiesis that are absent from the peripheral blood under physiological conditions. Their presence is associated with adverse outcomes in critically ill patients. This study aimed to evaluate the predictive value of nRBC on mortality in intensive care unit (ICU) patients with COVID-19 acute respiratory distress syndrome (ARDS).Material and methodsThis retrospective, observational cohort study analyzed data on 206 ICU patients diagnosed with COVID-19 ARDS between March 2020 and March 2022. The primary endpoint was ICU mortality, and secondary endpoints included ICU and hospital stay lengths, ventilation hours, and the time courses of disease severity scores and clinical and laboratory parameters.ResultsAmong the included patients, 68.9% tested positive for nRBC at least once during their ICU stay. A maximum nRBC of 105 µl-1 had the highest accuracy in predicting ICU mortality (area under the curve of the receiver operating characteristic [AUCROC] 0.780, p < 0.001, sensitivity 69.0%, specificity 75.5%). Mortality was significantly higher among patients with nRBC >105 µl-1 than ≤105 µl-1 (86.5% vs. 51.3%, p = 0.008). Compared to patients negative for nRBC in their peripheral blood, those positive for nRBC required longer mechanical ventilation (127 [44 - 289] h vs. 517 [255 - 950] h, p < 0.001), ICU stays (12 [8 – 19] vs. 27 [13 – 51] d, p < 0.001), and hospital stays (19 [12 - 29] d vs. 31 [16 - 58] d, p < 0.001). Peak Sepsis-related Organ Failure Assessment (SOFA), Simplified Acute Physiology Score, PaO2/FiO2, interleukin-6, and procalcitonin values were reached before the peak nRBC level. However, the predictive performance of the SOFA (AUCROC 0.842, p < 0.001) was considerably improved when a maximum SOFA score >8 and nRBC >105 µl-1 were combined.DiscussionnRBC predict ICU mortality and indicate disease severity among patients with COVID-19 ARDS, and they should be considered a clinical alarm signal for a worse outcome. nRBC are a late predictor of ICU mortality compared to other established clinical scoring systems and laboratory parameters but improve the prediction accuracy when combined with the SOFA score.

Abstract Right ventricular (RV) function and its adaptation to increased afterload [RV–pulmonary arterial (PA) coupling] are crucial in various types of pulmonary hypertension, determining symptomatology and outcome. In the course of disease progression and increasing afterload, the right ventricle undergoes adaptive remodelling to maintain right‐sided cardiac output by increasing contractility. Exhaustion of compensatory RV remodelling (RV–PA uncoupling) finally leads to maladaptation and increase of cardiac volumes, resulting in heart failure. The gold‐standard measurement of RV–PA coupling is the ratio of contractility [end‐systolic elastance (Ees)] to afterload [arterial elastance (Ea)] derived from RV pressure–volume loops obtained by conductance catheterization. The optimal Ees/Ea ratio is between 1.5 and 2.0. RV–PA coupling in pulmonary hypertension has considerable reserve; the Ees/Ea threshold at which uncoupling occurs is estimated to be ~0.7. As RV conductance catheterization is invasive, complex, and not widely available, multiple non‐invasive echocardiographic surrogates for Ees/Ea have been investigated. One of the first described and best validated surrogates is the ratio of tricuspid annular plane systolic excursion to estimated pulmonary arterial systolic pressure (TAPSE/PASP), which has shown prognostic relevance in left‐sided heart failure and precapillary pulmonary hypertension. Other RV–PA coupling surrogates have been formed by replacing TAPSE with different echocardiographic measures of RV contractility, such as peak systolic tissue velocity of the lateral tricuspid annulus (S′), RV fractional area change, speckle tracking‐based RV free wall longitudinal strain and global longitudinal strain, and three‐dimensional RV ejection fraction. PASP‐independent surrogates have also been studied, including the ratios S′/RV end‐systolic area index, RV area change/RV end‐systolic area, and stroke volume/end‐systolic volume. Limitations of these non‐invasive surrogates include the influence of severe tricuspid regurgitation (which can cause distortion of longitudinal measurements and underestimation of PASP) and the angle dependence of TAPSE and PASP. Detection of early RV remodelling may require isolated analysis of single components of RV shortening along the radial and anteroposterior axes as well as the longitudinal axis. Multiple non‐invasive methods may need to be applied depending on the level of RV dysfunction. This review explains the mechanisms of RV (mal)adaptation to its load, describes the invasive assessment of RV–PA coupling, and provides an overview of studies of non‐invasive surrogate parameters, highlighting recently published works in this field. Further large‐scale prospective studies including gold‐standard validation are needed, as most studies to date had a retrospective, single‐centre design with a small number of participants, and validation against gold‐standard Ees/Ea was rarely performed.

Background Right ventricular (RV) diastolic dysfunction may be prognostic in pulmonary hypertension (PH). However, its assessment is complex and relies on conductance catheterisation. We aimed to evaluate echocardiography-based parameters as surrogates of RV diastolic function, provide validation against the gold standard, end-diastolic elastance (Eed), and define the prognostic impact of echocardiography-derived RV diastolic dysfunction. Methods Patients with suspected PH who underwent right heart catheterisation including conductance catheterisation were prospectively recruited. In this study population, an echocardiography-based RV diastolic function surrogate was derived. Survival analyses were performed in patients with precapillary PH in the Giessen PH Registry, with external validation in patients with pulmonary arterial hypertension at Sapienza University (Rome). Results In the derivation cohort (n=61), the early/late diastolic tricuspid inflow velocity ratio (E/A) and early tricuspid inflow velocity/early diastolic tricuspid annular velocity ratio (E/e′) did not correlate with Eed (p>0.05). Receiver operating characteristic analysis revealed a large area under the curve (AUC) for the peak lateral tricuspid annulus systolic velocity/right atrial area index ratio (S′/RAAi) to detect elevated Eed (AUC 0.913, 95% confidence interval (CI) 0.839–0.986) and elevated end-diastolic pressure (AUC 0.848, 95% CI 0.699–0.998) with an optimal threshold of 0.81 m2·s−1·cm−1. Subgroup analyses demonstrated a large AUC in patients with preserved RV systolic function (AUC 0.963, 95% CI 0.882–1.000). Survival analyses confirmed the prognostic relevance of S′/RAAi in the Giessen PH Registry (n=225) and the external validation cohort (n=106). Conclusions Our study demonstrates the usefulness of echocardiography-derived S′/RAAi for noninvasive assessment of RV diastolic function and prognosis in PH.

Background The impact of changes in Doppler‐derived kidney venous flow in heart failure (HF) is not well studied. We aimed to investigate the association of Doppler‐derived kidney venous stasis index (KVSI) and intrakidney venous‐flow (IKVF) patterns with adverse cardiorenal outcomes in patients with HF. Methods and Results In this observational cohort study, consecutive inpatients with HF referred to a nephrologist because of a history of diuretic resistance and abnormal kidney function (n=216) underwent spectral kidney assessments after admission (Doppler 1) and 25 to 35 days later (Doppler 2) to identify IKVF patterns (continuous/pulsatile/biphasic/monophasic) and KVSI levels. Cox proportional hazard regression models were used to evaluate the associations between KVSI/IKVF patterns at Doppler 1 as well as changes from Doppler 1 to Doppler 2 and risk of cardiorenal events up to 18 months after admission. Worsening HF or death occurred in 126 patients. Both baseline KVSI (hazard ratio [HR], 1.49 [95% CI, 1.37–1.61] per 0.1‐unit increase) and baseline IKVF pattern (HR, 2.47 [95% CI, 2.01–3.04] per 1 pattern severity increase) were significantly associated with worsening HF/death. Increases in both KVSI and IKVF pattern severity from Doppler 1 to 2 were also associated with an increased risk of worsening HF/death (HR, 3.00 [95% CI, 2.08–4.32] per 0.1‐unit increase change; and HR, 6.73 [95% CI, 3.27–13.86] per 1 pattern increase in severity change, respectively). Similar results were observed for kidney outcomes. Conclusions Baseline kidney venous flow predicted adverse cardiorenal events, and inclusion of serial kidney venous flow in cardiorenal risk stratification could facilitate clinical decision‐making for patients with HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03039959.

Up to 20% of all non-small cell lung cancer patients harbor tumor specific driver mutations that are effectively treated with tyrosine kinase inhibitors. However, for the rare EGFR deletion-insertion mutation of exon 18, there is very little evidence regarding the effectiveness of tyrosine kinase inhibitors. A particular challenge for clinicians in applying tyrosine kinase inhibitors is not only diagnosing a mutation but also interpreting rare mutations with unclear therapeutic significance. Thus, we present the case of a 65-year-old Caucasian male lung adenocarcinoma patient with an EGFR Exon 18 p.Glu709_Thr710delinsAsp mutation of uncertain therapeutic relevance. This patient initially received two cycles of standard platinum-based chemotherapy without any therapeutic response. After administration of Osimertinib as second line therapy, the patient showed a lasting partial remission for 12 months. Therapy related toxicities were limited to mild thrombocytopenia, which ceased after dose reduction of Osimertinib. To our knowledge, this is the first report of effective treatment of this particular mutation with Osimertinib. Hence, we would like to discuss Osimertinib as a viable treatment option in EGFR Exon 18 p.Glu709_Thr710delinsAsp mutated lung adenocarcinoma.

BackgroundCardiac interactions with organs such as the liver or kidneys have been described in different cardiovascular diseases. However, the clinical relevance of hepatorenal dysfunction in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We determined the association of hepatorenal dysfunction (measured using the Model for End-stage Liver Disease Sodium [MELDNa] score) with right heart function and survival in patients with CTEPH.MethodsWe analyzed all patients with CTEPH in the Giessen Pulmonary Hypertension Registry who had available MELDNa scores and were not taking vitamin K antagonists. The MELDNa score was calculated as MELD score − serum Na − (0.025 * MELD score * (140 − serum Na)) + 140; the MELD score was calculated as 10*(0.957*ln(creatinine)+0.378*ln(bilirubin)+1.12*ln(International Normalized Ratio))+6.43.ResultsSeventy-two patients were included (74% female; median [Q1, Q3] MELDNa: 9 [6, 11]). MELDNa correlated well with right atrial and ventricular function and pulmonary hemodynamics. Forward regression analysis revealed that hepatorenal dysfunction mainly depends on right atrial strain and tricuspid regurgitation, but not right ventricular systolic dysfunction. Hepatorenal dysfunction predicted mortality at baseline and follow-up (adjusted hazard ratios [95% confidence intervals] per unit increase of MELDNa: 1.6 [1.1, 2.4] and 1.8 [1.1, 2.9], respectively). Changes in hepatorenal function also predicted mortality.ConclusionHepatorenal dysfunction in CTEPH is primarily associated with venous congestion rather than cardiac forward failure. As a surrogate parameter for hepatorenal dysfunction, MELDNa is a simple method to identify at-risk patients at baseline and follow-up.

Abstract Background Persistent symptoms after initial COVID-19 infection are common and are frequently referred to by the umbrella terms “post-COVID syndrome” and “long COVID”. The sheer number of affected patients pose an increasing challenge to healthcare systems worldwide. To date, our understanding of the pathophysiology of the post-COVID syndrome remains poor and the extent to which persistent cardiopulmonary abnormalities contribute to the symptom complex is unclear. We sought to determine the presence and impact of cardiopulmonary sequelae after COVID-19 in longitudinal assessment. Methods We report on 71 patients who underwent comprehensive, longitudinal testing in regular intervals for up to 12 months after their initial COVID-19 diagnosis. Testing included pulmonary function testing, cardiopulmonary exercise testing, dedicated left and right heart echocardiography, lung ultrasonography, and cardiac MRI. Results Our results demonstrate that subjective quality of life after COVID-19 (EQ-5D visual acuity scale, VAS, 67.4 for patients treated as outpatient, 79.2 for patients admitted to the general floor, 71.8 for patients treated in an ICU) is not related to the severity of the initial infection. Maximal exercise capacity is also reduced (VO2max 79% predicted, SD ± 19%); however, this is driven in large parts by patients who had initially required ICU-level of care. The degree of objective reduction in exertion did not correlate with quality of life scores. Pulmonary function testing revealed mild and persistent reduction in DLCO over the first 12 months without significant restrictive or obstructive lung disease. Left and right heart function was intact with good RV function and intact RV/PA coupling, imaging findings suggestive of myocarditis were uncommon (7% of patients). Conclusion A reduction in exercise capacity after COVID-19 is common, but is most prominent in patients previously treated in the ICU and more likely related to deconditioning or fatigue than to cardiopulmonary impairment. Subjective quality of life scores are independent of the severity of initial infection and do not correlate with objective measures of cardiopulmonary function. In our cohort, persistent cardiopulmonary impairment after COVID-19 was uncommon. The post-COVID syndrome is unlikely to be the result of cardiopulmonary sequalae and may reflect a post-ICU syndrome in some. Trial registration Registered on clinicaltrials.gov (NCT04442789), Date: June 23, 2020

PurposeThe relevance of dual-energy computed tomography (DECT) for the detection of chronic thromboembolic pulmonary hypertension (CTEPH) still lies behind V/Q-SPECT in current clinical guidelines. Therefore, our study aimed to assess the diagnostic accuracy of DECT compared to V/Q-SPECT with invasive pulmonary angiogram (PA) serving as the reference standard.MethodsA total of 28 patients (mean age 62.1 years ± 10.6SD; 18 women) with clinically suspected CTEPH were retrospectively included. All patients received DECT with the calculation of iodine maps, V/Q-SPECT, and PA. Results of DECT and V/Q-SPECT were compared, and the percent of agreement, concordance (utilizing Cohen's kappa), and accuracy (kappa2) to PA were calculated. Furthermore, radiation doses were analyzed and compared.ResultsIn total, 18 patients were diagnosed with CTEPH (mean age 62.4 years ± 11.0SD; 10 women) and 10 patients had other diseases. Compared to PA, accuracy and concordance for DECT were superior to V/Q-SPECT in all patients (88.9% vs. 81.3%; k = 0.764 vs. k = 0.607) and in CTEPH patients (82.4% vs. 70.1%; k = 0.694 vs. k = 0.560). Furthermore, the mean radiation dose was significantly lower for DECT vs. V/Q-SPECT (p = 0.0081).ConclusionIn our patient cohort, DECT is at least equivalent to V/Q-SPECT in diagnosing CTEPH and has the added advantage of significantly lower radiation doses in combination with simultaneous assessment of lung and heart morphology. Hence, DECT should be the subject of ongoing research, and if our results are further confirmed, it should be implemented in future diagnostic PH algorithms at least on par with V/Q-SPECT.

BackgroundVolume overload is often associated with clinical deterioration in precapillary pulmonary hypertension (PH). However, thorough assessment of volume overload is complex and therefore not routinely performed. We examined whether estimated plasma volume status (ePVS) is associated with central venous congestion and prognosis in patients with idiopathic pulmonary arterial hypertension (IPAH) or chronic thromboembolic PH (CTEPH).MethodsWe included all patients with incident IPAH or CTEPH enrolled in the Giessen PH Registry between January 2010 and January 2021. Plasma volume status was estimated using the Strauss formula.ResultsIn total, 381 patients were analyzed. Patients with high ePVS (≥4.7 vs.

Abstract Background Post-cardiac surgery acute kidney injury (AKI) is associated with increased mortality. A high-protein meal enhances the renal blood flow and glomerular filtration rate (GFR) and might protect the kidneys from acute ischemic insults. Hence, we assessed the effect of a preoperative high-oral protein load on post-cardiac surgery renal function and used experimental models to elucidate mechanisms by which protein might stimulate kidney-protective effects. Methods The prospective “Preoperative Renal Functional Reserve Predicts Risk of AKI after Cardiac Operation” study follow-up was extended to postoperative 12 months for 109 patients. A 1:2 ratio propensity score matching method was used to identify a control group (n = 214) to comparatively evaluate the effects of a preoperative protein load and standard care. The primary endpoints were AKI development and postoperative estimated GFR (eGFR) loss at 3 and 12 months. We also assessed the secretion of tissue inhibitor of metalloproteases-2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7), biomarkers implicated in mediating kidney-protective mechanisms in human kidney tubular cells that we exposed to varying protein concentrations. Results The AKI rate did not differ between the protein loading and control groups (13.6 vs. 12.3%; p = 0.5). However, the mean eGFR loss was lower in the former after 3 months (0.1 [95% CI − 1.4, − 1.7] vs. − 3.3 [95% CI − 4.4, − 2.2] ml/min/1.73 m2) and 12 months (− 2.7 [95% CI − 4.2, − 1.2] vs − 10.2 [95% CI − 11.3, − 9.1] ml/min/1.73 m2; p

Abstract Aims A method for estimating right ventricular ejection fraction (RVEF) from RV pressure waveforms was recently validated in an experimental model. Currently, cardiac magnetic resonance imaging (MRI) is the clinical reference standard for measurement of RVEF in pulmonary arterial hypertension (PAH). The present study was designed to test the hypothesis that the pressure‐based method can detect clinically significant reductions in RVEF as determined by cardiac MRI in patients with PAH. Methods and results RVEF estimates derived from analysis of RV pressure waveforms recorded during right heart catheterization (RHC) in 25 patients were compared with cardiac MRI measurements of RVEF obtained within 24 h. Three investigators blinded to cardiac MRI results independently performed pressure‐based RVEF estimation with the mean of their results used for comparison. Linear regression was used to assess correlation, and a receiver operator characteristic (ROC) curve was derived to define ability of the pressure‐based method to detect a maladaptive RV response, defined as RVEF

Background The brain-derived neurotrophic factor (BDNF) may promote development of pulmonary hypertension and right ventricular (RV) failure. However, BDNF plasma levels were decreased in patients with left ventricular (LV) failure. Therefore, we investigated BDNF plasma levels in pulmonary hypertension patients and the role of BDNF in mouse models of pulmonary hypertension and isolated RV failure. Methods BDNF plasma levels were correlated to pulmonary hypertension in two patient cohorts, including either post- and pre-capillary pulmonary hypertension patients (first cohort) or only pre-capillary pulmonary hypertension patients (second cohort). In the second cohort, RV dimensions and load-independent function were determined by imaging and pressure–volume catheter measurements, respectively. For induction of isolated RV pressure overload, heterozygous Bdnf knockout (Bdnf+/−) mice were subjected to pulmonary arterial banding (PAB). For induction of pulmonary hypertension, mice with inducible knockout of BDNF in smooth muscle cells (Bdnf/Smmhc knockout) were exposed to chronic hypoxia. Results Plasma BDNF levels were decreased in patients with pulmonary hypertension. Following adjustment for covariables, BDNF levels negatively correlated in both cohorts with central venous pressure. In the second cohort, BDNF levels additionally negatively correlated with RV dilatation. In animal models, BDNF downregulation attenuated RV dilatation in Bdnf+/−mice after PAB or hypoxic Bdnf/Smmhc knockout mice, although they developed pulmonary hypertension to a similar extent. Conclusions Similar to LV failure, circulating levels of BDNF were decreased in pulmonary hypertension patients, and low BDNF levels were associated with right heart congestion. Decreased BDNF levels did not worsen RV dilatation in animal models, and thus, may be the consequence, but not the cause of RV dilatation.

Background: Aspiration of stomach content or saliva in critical conditions—e.g., shock, intoxication, or resuscitation—can lead to acute lung injury. While various biomarkers in bronchoalveolar lavage fluids have been studied for diagnosing aspiration, none have been conclusively established as early indicators of lung damage. This study aims to evaluate the diagnostic value of pepsin, bile acid, and other biomarkers for detecting aspiration in an intensive care unit (ICU). Materials and methods: In this study, 50 ICU patients were enrolled and underwent intubation before admission. The evaluation of aspiration was based on clinical suspicion or documented instances of observed events. Tracheal secretion (TS) samples were collected within 6 h after intubation using sterile suction catheters. Additional parameters, including IL-6, pepsin, and bile acid, were determined for analysis. Pepsin levels were measured with an ELISA kit, while bile acid, uric acid, glucose, IL-6, and pH value in the tracheal secretion were analyzed using standardized lab methods. Results: The 50 patients admitted to the ICU with various diagnoses. The median survival time for the entire cohort was 52 days, and there was no significant difference in survival between patients with aspiration pneumonia (AP) and those with other diagnoses (p = 0.69). Among the AP group, the average survival time was 50.51 days (±8.1 SD; 95% CI 34.63–66.39), while patients with other diagnoses had a mean survival time of 32.86 days (±5.1 SD; 95% CI 22.9–42.81); the survival group comparison did not yield statistically significant results. The presence of pepsin or bile acid in TS patients did not significantly impact survival or the diagnosis of aspiration. The p-values for the correlations between pepsin and bile acid with the aspiration diagnosis were p = 0.53 and p > 0.99, respectively; thus, pepsin and bile acid measurements did not significantly affect survival outcomes or enhance the accuracy of diagnosing aspiration pneumonia. Conclusions: The early and accurate diagnosis of aspiration is crucial for optimal patient care. However, based on this study, pepsin concentration alone may not reliably indicate aspiration, and bile acid levels also show limited association with the diagnosis. Further validation studies are needed to assess the clinical usefulness and reliability of gastric biomarkers in diagnosing aspiration-related conditions. Such future studies would provide valuable insights for improving aspiration diagnosis and enhancing patient care.

Abstract The Pulmonary Vascular Research Institute GoDeep meta‐registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta‐registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty‐nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface‐based automated retrospective and prospective data transfer, GoDeep aims to provide in‐depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

Background: Parametric imaging has taken a steep rise in recent years and non-cardiac applications are of increasing interest. Therefore, the aim of our study was to assess right (RV) and left ventricular (LV) blood pool T1 and T2 values in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to control subjects and their correlation to pulmonary hemodynamic. Methods: 26 patients with CTEPH (mean age 64.8 years ± 12.8 SD; 15 female), who underwent CMR and right heart catheterization (RHC) before and 6-months after balloon pulmonary angioplasty (BPA), were retrospectively included. Ventricular blood pool values were measured, compared to control subjects (mean age 40.5 years ± 12.8 SD; 16 female) and correlated to invasive measures (CI, mPAP, PVR). Results: In both, control subjects and CTEPH patients, RVT1 and RVT2 were significantly reduced compared to LVT1 and LVT2. Compared to control subjects, RVT2 was significantly reduced in CTEPH patients (p = 0.0065) and increased significantly after BPA (p = 0.0048). Moreover, RVT2 was positively correlated with CI and negatively correlated with mPAP and PVR before (r = 0.5155, r = −0.2541, r = −0.4571) and after BPA (r = 0.4769, r = −0.2585, r = −0.4396). Conclusion: Ventricular blood pool T2 mapping might be novel non-invasive CMR imaging marker for assessment of disease severity, prognosis, follow-up and even therapy monitoring in PH.

A hallmark of acute respiratory distress syndrome (ARDS) is an accumulation of protein-rich alveolar edema that impairs gas exchange and leads to worse outcomes. Thus, understanding the mechanisms of alveolar albumin clearance is of high clinical relevance. Here, we investigated the mechanisms of the cellular albumin uptake in a three-dimensional culture of precision-cut lung slices (PCLS). We found that up to 60% of PCLS cells incorporated labeled albumin in a time- and concentration-dependent manner, whereas virtually no uptake of labeled dextran was observed. Of note, at a low temperature (4 °C), saturating albumin receptors with unlabeled albumin and an inhibition of clathrin-mediated endocytosis markedly decreased the endocytic uptake of the labeled protein, implicating a receptor-driven internalization process. Importantly, uptake rates of albumin were comparable in alveolar epithelial type I (ATI) and type II (ATII) cells, as assessed in PCLS from a SftpcCreERT2/+: tdTomatoflox/flox mouse strain (defined as EpCAM+CD31−CD45−tdTomatoSPC−T1α+ for ATI and EpCAM+CD31−CD45−tdTomatoSPC+T1α− for ATII cells). Once internalized, albumin was found in the early and recycling endosomes of the alveolar epithelium as well as in endothelial, mesenchymal, and hematopoietic cell populations, which might indicate transcytosis of the protein. In summary, we characterize albumin uptake in alveolar epithelial cells in the complex setting of PCLS. These findings may open new possibilities for pulmonary drug delivery that may improve the outcomes for patients with respiratory failure.

BackgroundPulmonary hypertension (PH) is an established risk factor in patients with heart failure (HF). However, right heart catheterisation (RHC) and vasoreactivity testing (VRT) are not routinely recommended in these patients.MethodsThe primary objective of the present study was to explore the impact of VRT using sublingual glyceryl trinitrate (GTN) on transplant/ventricular assist device-free survival in HF patients with post-capillary PH. RHC parameters were correlated retrospectively with the primary outcome.ResultsThe cohort comprised 154 HF patients with post-capillary PH undergoing RHC with GTN-VRT at a tertiary heart failure centre. Multiple parameters were associated with survival. After adjustment for established prognosis-relevant clinical variables from the MAGGIC Score, variables with the most relevant odds ratios (OR) obtained after GTN-VRT were: calculated effective pulmonary arterial (PA) elastance (adjusted OR 2.26, 95%CI 1.30–3.92; p = 0.004), PA compliance (PAC-GTN; adjusted OR 0.45, 95%CI 0.25–0.80; p = 0.006), and total pulmonary resistance (adjusted OR 2.29, 95%CI 1.34–3.93; p = 0.003). Forest plot analysis including these three variables as well as PAC at baseline, delta PAC, and the presence of combined post- and pre-capillary PH revealed prognostic superiority of PAC-GTN, which was confirmed by Kaplan-Meier analysis.ConclusionsIn our cohort of symptomatic HF patients with post-capillary PH, improved PAC after administration of GTN was associated with survival independent of established hemodynamic and clinical risk factors. VRT using GTN may be better described as unloading test due to GTN's complex effects on the circulation. This could be used for advanced prognostication and should be investigated in further studies.

BackgroundThe relevance of cor pulmonale in COPD and pulmonary hypertension due to COPD (PH-COPD) is incompletely understood. We aimed to investigate the relationship of right ventricular-pulmonary arterial (RV-PA) uncoupling with disease severity in COPD, and the relationship of RV-PA uncoupling and use of targeted PH therapies with mortality in PH-COPD.MethodsWe retrospectively analyzed 231 patients with COPD without PH and 274 patients with PH-COPD. COPD was classified according to GOLD stages and the modified Medical Research Council dyspnoea scale. PH was categorized as mild-to-moderate or severe. RV-PA uncoupling was assessed as the echocardiographic tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio.ResultsOf the cohort with COPD without PH, 21, 58, 54 and 92 were classified as GOLD I, II, III and IV, respectively. Patients in advanced GOLD stages and those with severe dyspnoea showed significantly decreased TAPSE/PASP.Of the PH-COPD cohort, 144 had mild-to-moderate PH and 130 had severe PH. During follow-up, 126 patients died. In univariate Cox regression, TAPSE/PASP and 6-min walk distance (6MWD; 10 m increments) predicted survival [hazard ratios (95% CI): 0.12 (0.03–0.57) and 0.95 (0.93–0.97), respectively]; notably, PH severity and simplified European Society of Cardiology/European Respiratory Society risk stratification did not. Among patients in the lowest or intermediate tertiles of TAPSE/PASP and 6MWD, those with targeted PH therapy had higher survival than those without (53 vs. 17% at 3 years).ConclusionCor pulmonale (decreased TAPSE/PASP and 6MWD) is associated with disease severity in COPD and predicts outcome in PH-COPD.

Background: Right atrial (RA) function has emerged as an important determinant of outcome in pulmonary arterial hypertension (PAH). However, studies exploring RA function after initiation of specific pulmonary vascular treatment and its association with outcome in patients with incident PAH are lacking.Methods: RA peak longitudinal strain (PLS), passive strain (PS), and peak active contraction strain (PACS) were retrospectively assessed in 56 treatment-naïve patients with PAH at baseline and during follow-up after initiation of specific monotherapy or combination therapy. Patients were grouped according to their individual RA functional response to treatment, based on change from baseline (Δ): worsened (first Δ-tertile), stable (second Δ-tertile), and improved (third Δ-tertile). The Spearman's rho correlation and linear regression analysis were used to determine associations. Time to clinical worsening (defined as deterioration of functional class or 6-min walking distance, disease-related hospital admission, or death) was measured from the follow-up assessment. The association of RA functional treatment response with time to clinical worsening was assessed using the Kaplan–Meier and the Cox regression analyses.Results: Median (interquartile range) time to echocardiographic follow-up was 11 (9–12) months. Of the 56 patients, 37 patients (66%) received specific dual or triple combination therapy. Δ RA PLS during follow-up was significantly associated with changes in key hemodynamic and echocardiographic parameters. The change of pulmonary vascular resistance, right ventricular (RV) end-systolic area, and global longitudinal strain were independently associated with Δ RA PLS. The median time to clinical worsening after echocardiographic follow-up was 6 (2–14) months [17 events (30%)]. In the multivariate Cox regression analysis, worsening of RA PLS was significantly associated with clinical deterioration (hazard ratio: 4.87; 95% CI: 1.26–18.76; p = 0.022). Patients with worsened RA PLS had a significantly poorer prognosis than those with stable or improved RA PLS (log-rank p = 0.012). By contrast, PS and PACS did not yield significant prognostic information.Conclusion: Treatment-naïve patients with PAH may show different RA functional response patterns to PAH therapy. These functional patterns are significantly associated with clinically relevant outcome measures. Improvements of RA function are driven by reductions of afterload, RV remodeling, and RV dysfunction.

Several acute and chronic lung diseases are associated with alveolar hypoventilation leading to accumulation of CO2 (hypercapnia). The β-subunit of the Na,K-ATPase plays a pivotal role in maintaining epithelial integrity by functioning as a cell adhesion molecule and regulating cell surface stability of the catalytic α-subunit of the transporter, thereby, maintaining optimal alveolar fluid balance. Here, we identified the E3 ubiquitin ligase for the Na,K-ATPase β-subunit, which promoted polyubiquitination, subsequent endocytosis and proteasomal degradation of the protein upon exposure of alveolar epithelial cells to elevated CO2 levels, thus impairing alveolar integrity. Ubiquitination of the Na,K-ATPase β-subunit required lysine 5 and 7 and mutating these residues (but not other lysines) prevented trafficking of Na,K-ATPase from the plasma membrane and stabilized the protein upon hypercapnia. Furthermore, ubiquitination of the Na,K-ATPase β-subunit was dependent on prior phosphorylation at serine 11 by protein kinase C (PKC)-ζ. Using a protein microarray, we identified the tumor necrosis factor receptor-associated factor 2 (TRAF2) as the E3 ligase driving ubiquitination of the Na,K-ATPase β-subunit upon hypercapnia. Of note, prevention of Na,K-ATPase β-subunit ubiquitination was necessary and sufficient to restore the formation of cell-cell junctions under hypercapnic conditions. These results suggest that a hypercapnic environment in the lung may lead to persistent epithelial dysfunction in affected patients. As such, the identification of the E3 ligase for the Na,K-ATPase may provide a novel therapeutic target, to be employed in patients with acute or chronic hypercapnic respiratory failure, aiming to restore alveolar epithelial integrity.

Mitochondrial and immune cell dysfunction contributes to the development of pulmonary arterial hypertension (PAH). We thus aimed to investigate mitochondrial respiration and mitochondrial gene expression patterns in the peripheral blood mononuclear cells (PBMC) of patients with idiopathic and hereditary PAH and their correlation to disease parameters. Mitochondrial respiration determined using high-resolution respirometry was not significantly different in PBMC when comparing an outpatient cohort of PAH patients with healthy controls. However, when directly comparing mitochondrial respiration to the hemodynamic parameters of an inpatient PAH cohort, mitochondrial respiration negatively correlated with pulmonary vascular resistance (PVR) and positively correlated with the cardiac index (CI). Furthermore, microarray analysis shows upregulation of mitochondrial erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), as well as the regulation of genes involved in iron and heme metabolism, in the PBMC of patients with PAH, with ALAS2 upregulation in PAH patients being confirmed on the protein level. Multiple regression analysis with age and gender as confounders showed that both PVR and hemoglobin content negatively correlated with maximal respiration. Therefore, we conclude that mitochondrial function in the PBMC of PAH patients is affected by disease severity. However, further studies to investigate cell-type-specific alterations and functional consequences are necessary.

Background: Currently an echocardiographic threshold for the tricuspid regurgitation gradient (TRG) of > 31 mmHg is recommended for screening for pulmonary hypertension (PH). Invasively diagnosed PH was recently redefined as mean pulmonary arterial pressure (mPAP) > 20 mmHg instead of ≥ 25 mmHg. We investigated the ability of TRG to screen for the new PH-definition. Methods: Retrospective assessment of echocardiography and right heart catheterisation data from 1572 patients entering the Giessen PH-Registry during 2008–2018. Accuracy of different TRG thresholds and other echocardiographic parameters was evaluated using receiver operating characteristic curves. Findings: 1264 patients fulfilled the new PH-definition. Positive (PPV) and negative predictive values and accuracy of TRG > 46 mmHg were 95%, 39%, and 73%, respectively, for the new PH-definition. Lowering the TRG cut-off to 31 mmHg and below worsened PPV to ≤ 89%. The PPV of TRG for pre-capillary PH (mPAP > 20 mmHg and pulmonary vascular resistance ≥ 3 Wood Units) was ≤ 85%. In patients with TRG ≤ 46 mmHg, tricuspid annular plane systolic excursion/TRG and TRG/right ventricular outflow tract acceleration time were superior to TRG in screening for newly defined pre-capillary PH. Interpretation: In patients with suspected PH referred to a tertiary care centre, the PPV of TRG to meet the new PH-definition depended strongly on the TRG cut-off used. Our data do not support lowering the TRG cut-off. Combining TRG with other echocardiographic parameters might improve the validity of echocardiographic screening for PH.

Coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome (ARDS) is associated with high mortality. Lung-protective ventilation is the current standard of care in patients with ARDS, but it might lead to hypercapnia, which is independently associated with worse outcomes. Extracorporeal carbon dioxide removal (ECCO2R) has been proposed as an adjuvant therapy to avoid progression of clinical severity and limit further ventilator-induced lung injury, but its use in COVID-19 has not been described yet. Acute kidney injury requiring renal replacement therapy (RRT) is common among critically ill COVID-19 patients. In centers with available dialysis, low-flow ECCO2R (

In 301 treatment-naïve patients with pulmonary arterial hypertension stratified by the European Society of Cardiology/European Respiratory Society risk score, further stratification of intermediate-risk patients based on six-minute walk distance and the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio identified a subset with mortality rates comparable to low-risk patients.

Pulmonary hypertension is frequently underdiagnosed, and referral is delayed with subsequent impact on outcomes. During the SARS-CoV-2 pandemic, restrictions on daily life and changes in hospitals' daily routine care were introduced in Germany. This multi-centre study provides evidence for a negative influence of these restrictions on patient care in pulmonary hypertension expert referral centres.

Right ventricular (RV) dyssynchrony has been related to outcome in pulmonary arterial hypertension. Prospectively, we performed echocardiography with measurement of right ventricular dyssynchrony and pressure–volume loop catheterization in 27 pulmonary arterial hypertension patients. Afterload and diastolic function emerged as determinates of wall stress, which results in dyssynchrony.

Implantable infusion pumps might improve the convenience and safety of intravenous treprostinil for pulmonary arterial hypertension. The LENUS Pro® pump (approved in Europe) has a fixed flow rate. Based on 126 pumps and 2853 refills, we retrospectively analyzed the actual flow rate from 09/2010 to 09/2018. A relevant flow rate variance is evident after three years; therefore, flow rate monitoring and dose adjustment are mandatory.

Background Persistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography. Methods and Results We enrolled 205 patients with suspected or prediagnosed pulmonary hypertension (PH) undergoing right heart catheterization. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary hemodynamics, echocardiography, renal function, intra‐abdominal pressure, and neurohormones and hydration status. Four spectral Doppler intrarenal venous flow patterns and a novel renal venous stasis index (RVSI) were defined. We evaluated PH‐related morbidity using the Cox proportional hazards model for the composite end point of PH progression (hospitalization for worsening PH, lung transplantation, or PH‐specific therapy escalation) and all‐cause mortality for 1‐year after discharge. The prognostic utility of RVSI and intrarenal venous flow patterns was compared using receiver operating characteristic curves. RVSI increased in a graded fashion across increasing severity of intrarenal venous flow patterns (P

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (

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.

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

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.

With rising altitude the partial pressure of oxygen falls. This phenomenon leads to hypobaric hypoxia at high altitude. Since more than 140 million people permanently live at heights above 2500 m and more than 35 million travel to these heights each year, understanding the mechanisms resulting in acute or chronic maladaptation of the human body to these circumstances is crucial. This review summarizes current knowledge of the body’s acute response to these circumstances, possible complications and their treatment, and health care issues resulting from long-term exposure to high altitude. It furthermore describes the characteristic mechanisms of adaptation to life in hypobaric hypoxia expressed by the three major ethnic groups permanently dwelling at high altitude. We additionally summarize current knowledge regarding possible treatment options for hypoxia-induced pulmonary hypertension by reviewing in vitro, rodent, and human studies in this area of research.

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.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.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.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.