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Tabakrauchen ist in Deutschland weitverbreitet. Sorge bereitet zuletzt ein Anstieg rauchender Jugendlicher und junger Erwachsener. Der hohen Prävalenz stehen die im internationalen Vergleich unzureichenden präventiven Maßnahmen in Deutschland konträr gegenüber. Das Rauchverhalten sollte analog einem Vitalzeichen immer erfragt und dokumentiert werden. Bei allen Rauchenden sollte unabhängig von Kontaktanlass und Motivation eine niedrigschwellige Kurzberatung erfolgen, beispielsweise nach dem ABC-Ansatz („ask, brief advice, cessation“). Für den Erfolg einer Entwöhnung ist neben wiederholten Gesprächen und der Vermittlung an weiterführende Angebote der Einsatz einer Nikotinersatztherapie bzw. medikamentösen Behandlung essenziell. Die Kombination von lang und kurz wirksamen Nikotinersatzpräparaten verdoppelt die Erfolgsrate. Elektronische Nikotininhalationssysteme werden für die Tabakentwöhnung nicht empfohlen.

•About one-third of clinically healthy agers already have a subclinical atherosclerotic plaque.•Older age and higher blood pressure, which is not classified as hypertension, are positively associated with subclinical atherosclerotic plaques.•mTregs but not the total population of Tregs are linked to a subclinical stage of atherosclerosis and could be considered as a biomarker.•The subtypes mTregs and rTregs are furthermore linked to factors such as low-density lipoprotein (LDL) or cardio respiratory fitness and may be additional diagnostic indicators.

Plants and other organisms, but not insects or vertebrates, express the auxiliary respiratory enzyme alternative oxidase (AOX) that bypasses mitochondrial respiratory complexes III and/or IV when impaired. Persistent expression of AOX from Ciona intestinalisin mammalian models has previously been shown to be effective in alleviating some metabolic stresses produced by respiratory chain inhibition while exacerbating others. This implies that chronic AOX expression may modify or disrupt metabolic signaling processes necessary to orchestrate adaptive remodeling, suggesting that its potential therapeutic use may be confined to acute pathologies, where a single course of treatment would suffice. One possible route for administering AOX transiently is AOX-encoding nucleic acid constructs. Here we demonstrate that AOX-encoding chemically-modified RNA (cmRNA), sequence-optimized for expression in mammalian cells, was able to support AOX expression in immortalized mouse embryonic fibroblasts (iMEFs), human lung carcinoma cells (A549) and primary mouse pulmonary arterial smooth muscle cells (PASMCs). AOX protein was detectable as early as 3 h after transfection, had a half-life of ~4 days and was catalytically active, thus supporting respiration and protecting against respiratory inhibition. Our data demonstrate that AOX-encoding cmRNA optimized for use in mammalian cells represents a viable route to investigate and possibly treat mitochondrial respiratory disorders.

Hintergrund: Pulmonale Manifestationen sind sehr häufige Folgeerscheinungen nach einer Severe-acute-respiratory-syndrome-coronavirus-type-2(SARS-CoV-2)-Infektion, die unter dem Begriff Long-COVID-Syndrom (COVID„coronavirus disease“) zusammengefasst werden. Ziel und Methoden: Zusammenfassung der aktuellen Literatur zu den pulmonalen Manifestationen mit einem Fokus auf Expertenempfehlungen. Ergebnisse: Dyspnoe ist nach der chronischen Fatigue das häufigste Symptom bei Patienten mit Long-COVID-Syndrom. Auffällige Befunde finden sich vor allem nach schwerem akutem COVID-19-Verlauf und beinhalten radiologische Veränderungen im Sinne interstitieller Lungenerkrankungen, restriktive lungenfunktionelle Befunde und Einschränkungen der Diffusionskapazität als häufigsten pathologischen Befund. Obwohl sich sowohl Beschwerden als auch pathologische pulmonale Befunde im Verlauf bessern, können einige Patienten noch Monate nach der akuten Infektion unter Auffälligkeiten leiden. Dabei ist die Relevanz der pathologischen Befunde sowie eine Beteiligung funktioneller respiratorischer Einschränkungen, einer kardiopulmonalen Dekonditionierung, nichtsomatischer Ursachen und vorbestehender Erkrankungen aktuell unklar. Die diagnostische Abklärung fokussiert entsprechend auf Risikopatienten und schließt neben einer bildgebenden und lungenfunktionellen Abklärung eine Belastungsuntersuchung und bei unklaren Befunden eine Echokardiographie zur Diagnose einer pulmonalvaskulären Komponente ein. Die therapeutischen Möglichkeiten beinhalten aktuell die leitliniengerechte Therapie von Ursachen der Beschwerden (beispielsweise interstitielle Lungenerkrankungen, Husten) und Rehabilitationsmaßnahmen. Schlussfolgerung: Das aktuelle Wissen zum Krankheitsbild wird ständig erweitert, allerdings existieren aufgrund mangelnder Studienlage noch keine evidenzbasierten Leitlinien zur Diagnostik und Therapie pulmonaler Manifestationen beim Long-COVID-Syndrom.

Supplemental Digital Content is available in the text.

The right ventricle (RV) function plays a crucial role in the prognosis and functional outcome of PAH (Pulmonary Arterial Hypertension) patients. However, RV remodeling and its underlying mechanisms in PAH, and the molecular phenotype of RV in different disease conditions are poorly understood. Therefore, we designed this study to deeply investigate molecular changes underlying right ventricular remodeling and dysfunction in PAH. To this aim, we generated RNA-seq data from 40 patients' RV tissues, clinically classified in adaptive versus maladaptive RV hypertrophy. Using an unsupervised clustering-based analysis, we identified “early” and “late” subgroups in both diseased RV states, associated with patients’ hemodynamic profiles. We then demonstrated that the compensated RV is characterized by an upregulation of cell cycle-associated genes and mitochondrial respiration, whereas excessive levels of extracellular matrix components were central in the decompensation phase. However, dysregulation of fatty acid β-oxidation characterized the early decompensation phase. Furthermore, a comparative analysis from 30 RV samples of monocrotaline (MCT)-induced rat model largely confirmed the stage-specific molecular phenotypes, along with subgroups identification. Finally, we assessed the circulating levels of several dysregulated proteins in two independent cohorts of PAH patients and introduced a panel of five ECM-related proteins that had a significant alteration in patients with compensated vs. decompensated RV in both cohorts. Among those, NID1, C1QTNF1, and CRTAC1 demonstrated higher importance in predicting the development of maladaptive RV hypertrophy in both cohorts, while the correlation of their expression with cardiac functions confirmed their potential biomarker capacity in the prognosis of PAH-associated RV hypertrophy and failure. In conclusion, this comprehensive transcriptome study revealed new subgroups of human RV hypertrophy beyond the clinical measurements, while combination with proteome analysis proposed a panel of potential PAH biomarkers related to patients' RV function. Furthermore, our comparative analysis of two species supports the relevance of current animal models to explore new targets.

Vasoreactivity testing with inhaled NO is recommended for pulmonary arterial hypertension (PAH) because of its therapeutic and prognostic value. Sildenafil has acute pulmonary vasodilating properties, but its diagnostic and prognostic impact in PAH is unknown. Our objective was to compare acute vasodilating responses to sildenafil and those to NO during right heart catheterization and also their prognostic values in patients with PAH. Ninety-nine patients with idiopathic PAH and 99 with associated PAH underwent vasoreactivity testing with NO and sildenafil. Only mild adverse effects of sildenafil, in the form of hypotension, were observed, at a rate of 4.5%. The acute responder rate was 8.1% for NO and 11.6% for sildenafil. The NO-induced response in mean pulmonary arterial pressure and cardiac output correlated with the response to sildenafil. Thirteen patients were long-term responders to calcium channel blockers (CCBs), and 3 of them were correctly identified by acute vasoreactivity test with both drugs. The specificity of the vasoreactivity test for identifying long-term CCB responders was 88.9% for NO and 85.1% for sildenafil testing. A trend toward better survival was found in sildenafil and NO responders, compared with nonresponders. Use of sildenafil for vasoreactivity testing is safe. Sildenafil may be useful as alternative vasoreactivity-testing agent, identifying the same number of long-term CCB responders as NO. However, NO seems to be a more ideal testing drug because of its pharmacologic properties. Moreover, sildenafil vasoreactivity testing might contribute to an improved estimate of prognosis among patients with PAH.

Vasoreactivity testing with inhaled NO is recommended for pulmonary arterial hypertension (PAH) because of its therapeutic and prognostic value. Sildenafil has acute pulmonary vasodilating properties, but its diagnostic and prognostic impact in PAH is unknown. Our objective was to compare acute vasodilating responses to sildenafil and those to NO during right heart catheterization and also their prognostic values in patients with PAH. Ninety-nine patients with idiopathic PAH and 99 with associated PAH underwent vasoreactivity testing with NO and sildenafil. Only mild adverse effects of sildenafil, in the form of hypotension, were observed, at a rate of 4.5%. The acute responder rate was 8.1% for NO and 11.6% for sildenafil. The NO-induced response in mean pulmonary arterial pressure and cardiac output correlated with the response to sildenafil. Thirteen patients were long-term responders to calcium channel blockers (CCBs), and 3 of them were correctly identified by acute vasoreactivity test with both drugs. The specificity of the vasoreactivity test for identifying long-term CCB responders was 88.9% for NO and 85.1% for sildenafil testing. A trend toward better survival was found in sildenafil and NO responders, compared with nonresponders. Use of sildenafil for vasoreactivity testing is safe. Sildenafil may be useful as alternative vasoreactivity-testing agent, identifying the same number of long-term CCB responders as NO. However, NO seems to be a more ideal testing drug because of its pharmacologic properties. Moreover, sildenafil vasoreactivity testing might contribute to an improved estimate of prognosis among patients with PAH.

Abstract Hemodynamic measurements provide important parameters for determining prognosis and therapy in patients with pulmonary arterial hypertension (PAH). Current guidelines do not incorporate the possible predictive value of individual changes in hemodynamic variables during the disease time course, and there is no consensus about the time point for hemodynamic reevaluation. We aimed to assess the long-term prognostic value of short-term changes in hemodynamic parameters. The study included 122 patients with PAH from the Giessen Pulmonary Hypertension Registry who underwent hemodynamic evaluation at baseline and at 16 weeks (±2.5 standard deviations [SDs]; range: 4–29 weeks) after initial assessment. At baseline, mean pulmonary vascular resistance (PVR) was 1,109 dyn s cm−5, and 82% of patients were in World Health Organization (WHO) functional class III or IV. Fifty patients died, and 2 underwent lung transplantation during long-term observation (≤10 years; mean: 4.7 years). Kaplan-Meier estimates for transplant-free survival were 93.3%, 76.1%, 57.8%, and 53.1% at 1, 3, 5, and 7 years, respectively. When assigned to prognostic groups, improvements in cardiac output of >0.22 L min−1 (hazard ratio [HR]: 2.05; ) and a decrease in PVR of >176 dyn s cm−5 (HR: 1.89; ) at 4–29 weeks were associated with long-term transplant-free survival. Changes in mean pulmonary arterial pressure did not predict long-term prognosis. Of 2 noninvasive parameters assessed in this selected patient group, change in WHO functional class, but not in 6-minute walk distance, predicted long-term prognosis. Short-term assessment of changes in hemodynamic parameters at after initial invasive evaluation is useful to determine long-term prognosis in patients with PAH.

Hemodynamic measurements provide important parameters for determining prognosis and therapy in patients with pulmonary arterial hypertension (PAH). Current guidelines do not incorporate the possible predictive value of individual changes in hemodynamic variables during the disease time course, and there is no consensus about the time point for hemodynamic reevaluation. We aimed to assess the long-term prognostic value of short-term changes in hemodynamic parameters. The study included 122 patients with PAH from the Giessen Pulmonary Hypertension Registry who underwent hemodynamic evaluation at baseline and at 16 weeks (±2.5 standard deviations [SDs]; range: 4–29 weeks) after initial assessment. At baseline, mean pulmonary vascular resistance (PVR) was 1,109 dyn s cm−5, and 82% of patients were in World Health Organization (WHO) functional class III or IV. Fifty patients died, and 2 underwent lung transplantation during long-term observation (≤10 years; mean: 4.7 years). Kaplan-Meier estimates for transplant-free survival were 93.3%, 76.1%, 57.8%, and 53.1% at 1, 3, 5, and 7 years, respectively. When assigned to prognostic groups, improvements in cardiac output of >0.22 L min−1(hazard ratio [HR]: 2.05; P= 0.015) and a decrease in PVR of >176 dyn s cm−5(HR: 1.89; P= 0.044) at 4–29 weeks were associated with long-term transplant-free survival. Changes in mean pulmonary arterial pressure did not predict long-term prognosis. Of 2 noninvasive parameters assessed in this selected patient group, change in WHO functional class, but not in 6-minute walk distance, predicted long-term prognosis. Short-term assessment of changes in hemodynamic parameters at 16 weeks ± 2.5 SDs after initial invasive evaluation is useful to determine long-term prognosis in patients with PAH.

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.

HIF2α-mediated gene expression enables the carotid body to respond to acute hypoxia.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

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.