Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio-protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto-/paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.

Increased adrenomedullin (ADM) levels are associated with various cardiac diseases such as myocardial infarction (MI). ADM is cleaved off from the full-length precursor protein proadrenomedullin (ProADM) during its posttranslational processing. To date, no biological effect of ProADM is reported, while ADM infusion leads to antiapoptotic effects and improved cardiac function. Using an MI mouse model, we found an induction of ProADM gene as well as protein expression during the early phase of MI. This was accompanied by apoptosis and increasing inflammation, which substantially influence the post-MI remodeling processes. Simulating ischemia in vitro, we demonstrate that ProADM expression was increased in cardiomyocytes and cardiac fibroblasts. Subsequently, we treated ischemic cardiomyocytes with either ProADM or ADM and found that both proteins increased survival. This effect was diminishable by blocking the ADM₁ receptor. To investigate whether ProADM and ADM play a role in the regulation of cardiac inflammation, we analyzed chemokine expression after treatment of cells with both proteins. While ProADM induced an expression of proinflammatory cytokines, thus promoting inflammation, ADM reduced chemokine expression. On leukocytes, both proteins repressed chemokine expression, revealing antiinflammatory effects. However, ProADM but not ADM dampened concurrent activation of leukocytes. Our data show that the full-length precursor ProADM is biologically active by reducing apoptosis to a similar extent as ADM. We further assume that ProADM induces local inflammation in affected cardiac tissue but attenuates exaggerated inflammation, whereas ADM has low impact. Our data suggest that both proteins are beneficial during MI by influencing apoptosis and inflammation. Significance Myocardial infarction (MI) is one of the leading causes of death worldwide and is characterized by apoptosis and inflammation. While increased adrenomedullin (ADM) levels after MI are associated with disease severity, ADM infusion leads to antiapoptotic effects, suggesting a self-protective mechanism. ADM is cleaved from a full‐length precursor protein (ProADM), a putatively inactive prohormone. Our data show that ProADM is biologically active by reducing apoptosis to a similar extent as ADM. In contrast to ADM, ProADM has proinflammatory effects on cardiac fibroblasts but antiinflammatory effects on activated leukocytes. We assume that ProADM induces local inflammation but attenuates exaggerated inflammation. Our data suggest that both proteins are beneficial during MI by regulating inflammation and reducing apoptosis of cardiomyocytes.

Purpose: Real-life effectiveness data on once-daily single-inhaler triple therapy (odSITT) with the inhaled corticosteroid fluticasone furoate (FF), the long-acting muscarinic antagonist umeclidinium (UMEC), and the long-acting β₂-agonist vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) are important to complement evidence from well-controlled randomized clinical trials. Effectiveness of odSITT was quantified by assessing health status and symptoms in usual care. Patients and Methods: ELLITHE was a single-country (Germany), multicenter, open-label, non-interventional effectiveness study between 2020 and 2022, evaluating the effect of treatment initiation with FF/UMEC/VI 100/62.5/25 μg once-daily via the ELLIPTA inhaler on improvements in clinical outcomes versus baseline in COPD patients. The primary endpoint was the change in the total COPD Assessment Test (CAT) score between baseline and month 12. Key secondary endpoints included change in CAT score over time, occurrence of exacerbations until month 12, changes in forced expiratory volume in one second (FEV₁), inhaler adherence, and safety. Results: Nine hundred and six patients were included (age 66.6 years, 55.6% male, mean FEV₁ 52.6% of predicted, mean CAT 21.5 units, 1.4 exacerbations/year pre-study). About 63.9% of patients were escalated from dual therapies, and 18% were switched from multiple-inhaler triple therapies. Reductions in CAT score at month 12 were statistically significant and above the threshold of clinical importance (− 2.6 units; p < 0.0001). CAT score also improved at interim visits. CAT improvements were more pronounced in patients with high baseline scores and better inhaler adherence. Exacerbations during follow-up were rare (0.2 events/year) compared to pre-study (1.4 events/year). FEV₁ was improved by 93 mL (p < 0.0001). No new safety effects were observed. Conclusion: In usual care, treatment with odSITT resulted in significant and clinically relevant improvements of CAT score and FEV₁ in COPD patients, regardless of the occurrence of exacerbations. These findings challenge the current guideline recommendations for SITT only in patients experiencing exacerbations.

Zusammenfassung: Studiendaten weisen auf Versorgungslücken im COPD-Langzeitmanagement mit Diskrepanzen zwischen Leitlinienempfehlungen und deren praktischer Umsetzung hin. Die Gründe sind nur unzureichend bekannt. Ziel der ELETHON-Arztbefragung war die Erfassung ärztlicher Einstellungen und Meinungen zu allgemeinen Konzepten der COPD-Therapie, und im Speziellen zur Initiierung einer inhalativen Dreifachtherapie.ELETHON war eine bundesweit durchgeführte Querschnittstudie im ambulanten Sektor bei Hausärzten und Pneumologen unter Verwendung eines strukturierten Fragebogens (17 geschlossene Single- bzw. Multiple-Choice-Fragen) zu den Themen Sekundärprävention, Erfassung von Exazerbationen, Therapieeskalation, Auswahl von inhalativen Dreifachtherapien und Prüfung des Therapieerfolgs bei COPD.Fragebögen von n=2028 Hausärzten (HA) und n=371 Pneumologen (FA) wurden ausgewertet. Beide Gruppen weisen der Sekundärprävention bei COPD einen hohen Stellenwert zu (HA/FA 76,4%/90,6%), mit Prüfung von Inhalationstechnik, Impfstatus und adäquater inhalativer Pharmakotherapie als wichtigste Bausteine. Aktivität/Rehabilitation wurde bei Hausärzten deutlich seltener genannt (48,3 vs. 84,5%). Exazerbationen und Symptomverschlechterung gelten als dominierende Parameter für eine Therapieeskalation, werden jedoch mehrheitlich unsystematisch erfasst. Als Schwelle wurden „Hospitalisierung“ und „≥2 ambulante Exazerbationen“ am häufigsten genannt. Eosinophile werden mehrheitlich nicht bestimmt. Bei der Auswahl von Dreifachtherapien werden Festkombinationen bevorzugt, die Verfügbarkeit im gleichen Inhalator wie eine Mono- oder duale Therapie als wichtig betont. Der Therapieerfolg wird anhand von Exazerbationen, Lebensqualität, Symptomen, Lungenfunktion und Bedarfsmedikation bewertet. Der COPD Assessment Test (CAT)-Score kommt nur bei wenigen HA/FA zum Einsatz.Die ELETHON-Arztbefragung zeigt Lücken im COPD-Management auf. Das Konzept der Sekundärprävention wird als wichtig angesehen, dennoch erfolgt eine Therapieeskalation eher spät. Die Bedeutung des Impfstatus deckt sich nicht mit aktuellen Impfquoten, nicht-pharmakologische Maßnahmen werden unzureichend genutzt. Die Erfassung von Exazerbationen und Symptomatik erfolgt unsystematisch; validierte Fragebögen und Eosinophile haben nur einen untergeordneten Stellenwert. ELETHON liefert wichtige Erkenntnisse zu Barrieren und versteckten Potenzialen im Versorgungsalltag der COPD bei Haus- und Fachärzten in Deutschland.