Empagliflozin reduces the risk of a broad spectrum of heart failure outcomes regardless of heart failure status at baseline

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Impact of Empagliflozin in Heart Failure With Reduced Ejection Fraction in Patients With Ischemic Versus Nonischemic Cause

Background Outcomes and treatment effects of therapy may vary according to the cause of heart failure (HF). Methods and Results In this post hoc analysis of the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, the effect of empagliflozin on cardiovascular and renal outcomes was assessed according to the cause of HF. The cause of HF was investigator reported and stratified as ischemic or nonischemic. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs. Of the 3730 patients enrolled, 1929 (51.7%) had ischemic cause. In the placebo arm, patients with ischemic cause of HF did not have a significantly higher risk of cardiovascular mortality (HR, 1.21 [95% CI, 0.90-1.63]) and hospitalization for HF (HR, 0.90 [95% CI, 0.72-1.12]) compared with nonischemic cause. Empagliflozin compared with placebo significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with ischemic and nonischemic cause (HR, 0.82 [95% CI, 0.68-0.99] for ischemic and HR, 0.67 [95% CI, 0.55-0.82] for nonischemic cause; P interaction=0.15). The benefit of empagliflozin on HF hospitalization, the renal composite end point, estimated glomerular filtration slope changes, and health status scores were also consistent in both groups without treatment by cause modification. Conclusions Empagliflozin offers cardiovascular and renal benefits in patients with heart failure with reduced ejection fraction regardless of the cause of HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977

Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial

Drugs that inhibit the sodium–glucose co‐transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new‐onset heart failure events by ≈30%. In addition, in the EMPA‐REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti‐hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR‐Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin–angiotensin system and neprilysin, beta‐blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time‐to‐first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all‐cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high‐risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR‐Reduced trial is well‐positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Background: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co‐transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large‐scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design: The EMPEROR‐Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co‐morbidities. Study aims: The primary endpoint is the time‐to‐first‐event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all‐cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR‐Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options

Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951)

Die dreidimensionale Struktur nativer Editosomen aus afrikanischen Trypanosomen

RNA-Editing im Mitochondrium afrikanischer Trypanosomen generiert durch die Insertion und Deletion von ausschließlich Uridylatresten aus kryptischen Transkripten translationskompetente mRNAs. Dieser posttranskriptionale Prozess wird durch einen als Editosom bezeichneten Ribonukleoproteinkomplex bestehend aus mRNA, gRNA und bis zu 20 Proteinen katalysiert. Während die RNA- und Proteinkomponenten des Editosoms identifiziert und charakterisiert sind, ist über dessen strukturelle Organisation sowie über dessen Assemblierung und Dissoziation wenig bekannt. In dieser Arbeit wurden Editosomen in unterschiedlichen Stadien der Editing-Reaktion durch tandem affinity purification unter physiologischen Bedingungen isoliert. Editosomen in der Initiations-, Prozessierungs- und Terminationsphase enthalten mRNA, gRNA und 12-15 Proteine in unterschiedlicher Zusammensetzung. Nur in der Prozessierungsphase der Editing-Reaktion konnten funktionale Editosomen isoliert werden. Editosomen in der Initiations- und Terminationsphase zeigten keine Aktivität. In allen Stadien der Editing-Reaktion liegen Editosomen unter steady state-Bedingungen sowohl als 20 S und 40 S Subpopulationen vor. Durch Transmissionselektronenmikroskopie wurden funktionale 20 S und 40 S Editosomen visualisiert. Durch eine als random conical tilt bezeichnete Methode wurde ihre dreidimensionale Struktur mit einer Auflösung von ~2 nm bestimmt. 20 S Editosomen haben eine elongierte, leicht gekrümmte Form. Sie bestehen aus zwei Subdomänen ähnlicher Größe, die über eine schmale Brücke miteinander verbunden sind. 20 S Editosomen haben eine Dimension von 21x15,5x14 nm, ein Molekulargewicht von 800±80 kDa, und einen Svedberg-Koeffizient von 21-26 S. 40 S Editosomen bestehen aus einer konvexen, elongierten Plattform, die sich an gegenüberliegenden Seiten zu globulären Domänen ausweitet. Auf die Plattform ist eine runde, asymmetrische Domäne aufgelagert. 40 S Editosomen haben eine Dimension von 26,5x20x17,5 nm, ein Molekulargewicht von 1,45±0,15 MDa, und einen Svedberg-Koeffizienten von 35-41 S. 20 S Editosomen stellen ein frühes Assemblierungsstadium der 40 S Editosomen dar. In einem dreidimensionalen Alignment konnte gezeigt werden, dass es sich bei den 20 S Editosomen um einen Teil der Plattform der 40 S Editosomen handelt. 20 S und 40 S Editosomen weisen ein ähnliches Proteinprofil auf, der Unterschied besteht hauptsächlich in ihrem RNA-Gehalt. 20 S Editosomen werden durch die Bindung von mRNA und gRNA in 40 S Editosomen konvertiert. Surface plasmon resonance-Messungen ergaben, dass sowohl gRNAs und mRNAs als auch ein gRNA/mRNA-Duplex mit einer Dissoziationskonstante im nanomolaren Bereich an 20 S Editosomen binden. Immunogold labeling-Experimente zeigten, dass 20 S Editosomen eine RNA-Bindestelle aufweisen

The structural landscape of native editosomes in African trypanosomes.

The majority of mitochondrial pre-messenger RNAs in African trypanosomes are substrates of a U-nucleotide-specific insertion/deletion-type RNA editing reaction. The process converts nonfunctional pre-mRNAs into translation-competent molecules and can generate protein diversity by alternative editing. High molecular mass protein complexes termed editosomes catalyze the processing reaction. They stably interact with pre-edited mRNAs and small noncoding RNAs, known as guide RNAs (gRNAs), which act as templates in the reaction. Editosomes provide a molecular surface for the individual steps of the catalytic reaction cycle and although the protein inventory of the complexes has been studied in detail, a structural analysis of the processing machinery has only recently been accomplished. Electron microscopy in combination with single particle reconstruction techniques has shown that steady state isolates of editosomes contain ensembles of two classes of stable complexes with calculated apparent hydrodynamic sizes of 20S and 35-40S. 20S editosomes are free of substrate RNAs, whereas 35-40S editosomes are associated with endogenous mRNA and gRNA molecules. Both complexes are characterized by a diverse structural landscape, which include complexes that lack or possess defined subdomains. Here, we summarize the consensus models and structural landmarks of both complexes. We correlate structural features with functional characteristics and provide an outlook into dynamic aspects of the editing reaction cycle

Trypanosoma brucei 20S editosomes have one RNA substrate-binding site and execute RNA unwinding activity.

Editing of mitochondrial pre-mRNAs in African trypanosomes generates full-length transcripts by the site-specific insertion and deletion of U nucleotides. The reaction is catalyzed by a 0.8MDa multienzyme complex, the editosome. Although the binding of substrate pre-edited mRNAs and cognate gRNAs represents the first step in the reaction cycle, the biochemical and biophysical details of the editosome/RNA interaction are not understood. Here we show that editosomes bind full-length substrate mRNAs with nanomolar affinity in a nonselective fashion. The complexes do not discriminate - neither kinetically nor thermodynamically - between different mitochondrial pre-mRNAs or between edited and unedited versions of the same transcript. They also bind gRNAs and gRNA/pre-mRNA hybrid RNAs with similar affinities and association rate constants. Gold-labeling of editosome-bound RNA in combination with transmission electron microscopy (TEM) identified a single RNA binding site per editosome. However, atomic force microscopy (AFM) of individual pre-mRNA/editosome complexes revealed that multiple editosomes can interact with one pre-mRNA. Lastly, we demonstrate a so far unknown activity of the editing machinery: editosome-bound RNA becomes unfolded by a chaperone-type RNA unwinding activity

Three-dimensional reconstruction of Trypanosoma brucei editosomes using single-particle electron microscopy.

RNA editing within the mitochondria of kinetoplastid protozoa is performed by a multicomponent -macromolecular machine known as the editosome. Editosomes are high molecular mass protein assemblies that consist of about 15-25 individual polypeptides. They bind pre-edited transcripts and convert them into translation-competent mRNAs through a biochemical reaction cycle of enzyme-catalyzed steps. At steady-state conditions, several distinct complexes can be purified from mitochondrial detergent lysates. They likely represent RNA editing complexes at different assembly stages or at different functional stages of the processing reaction. Due to their low cellular abundance, single-particle electron microscopy (EM) represents the method of choice for their structural characterization. This chapter describes a set of techniques suitable for the purification and structural characterization of RNA editing complexes by single-particle EM. The RNA editing complexes are isolated from the endogenous pool of mitochondrial complexes by tandem-affinity purification (TAP). Since the TAP procedure results in the isolation of a mixture of different RNA editing complexes, the isolates are further subjected to an isokinetic ultracentrifugation step to separate the complexes based on their sedimentation behavior. The use of the "GraFix" protocol is presented that combines mild chemical cross-linking with ultracentrifugation. Different sample preparation protocols including negative staining, cryo-negative staining, and unstained cryotechniques as well as the single-particle image processing of electron microscopical images are described

Four perspectives of landscape architectural thinking

Gedruckt erschienen im Universitätsverlag der TU Berlin, ISBN 978-3-7983-2914-0Was ist gute Landschaftsarchitektur? – Undine Giseke, Norbert Kühn, Cordula Loidl-Reisch und Jürgen Weidinger antworten in Auseinandersetzung mit den Konzepten Urbaner Metabolismus, Designing Urban Nature, Alltagstauglichkeit und Atmosphäre. Mit den Konzepten soll etwas verstanden und sollen zugleich Impulse für das Entwerfen gegeben werden. Das kennzeichnet eine besondere Form der Reflexion, die hier als landschaftsarchitektonisches Denken bezeichnet wird.What is good landscape architecture? — Undine Giseke, Norbert Kühn, Cordula Loidl-Reisch, and Jürgen Weidinger provide answers to this question, examining the concepts of urban metabolism, designing urban nature, suitability for daily use, and atmosphere. Their articles seek to bring clarity and provide inspiration for design work. This characterizes a special form of reflection that is referred to here as landscape-architectural thinking