Refine
Year of publication
- 2022 (3) (remove)
Document Type
- Article (2)
- Working Paper (1)
Language
- English (3)
Has Fulltext
- yes (3)
Is part of the Bibliography
- no (3)
Keywords
- ER stress (1)
- Eurozone (1)
- HIF-1α (1)
- HIF-2α (1)
- Maastricht criteria (1)
- Mild hypoxia (1)
- Stability and Growth Pact (1)
- UPR (1)
- fiscal rules (1)
- kidney function (1)
Institute
Background and purpose: Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.
Methods: The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD-EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m2. eGFR dynamics were classified based on two in-hospital values as “stable normal” (≥60 ml/min/1.73 m2), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m2), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m2), and “stable decreased” (<60 ml/min/1.73 m2). The composite endpoint (stroke, major bleeding, myocardial infarction, all-cause death) was assessed after 24 months. We estimated hazard ratios in confounder-adjusted models.
Results: Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m2 at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all-cause death (HR = 3.12, 95% CI = 1.63–5.98).
Conclusions: In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.
Debt levels in the eurozone have reached new record highs. The member countries have tried to cushion the economic consequences of the corona pandemic with a massive increase in government spending. End of 2021 public debt in relation to GDP will approach 100% on average. There are various calls to abolish or soften the Maastricht rules of limiting sovereign debt. We see the risk of a new sovereign debt crisis in this decade if it is not possible to bring public debt down to an acceptable level. Our new fiscal rule would be suitable and appropriate for this purpose, because obviously the Maastricht criteria have failed. In contrast to the rigid 3% Maastricht-criterion, our rule is flexible and it addresses the main problem: excessively high public debt ratios. And it lowers the existing incentives for highly indebted governments to exert expansionary pressure on monetary policy. If obeyed strictly, our rule reinforces the snowball effect and reduces the excessively high debt ratios within a manageable period, even if nominal growth is weak. This is confirmed by simulations with different scenarios as well as with the hypothetical application of the new fiscal rule to eurozone economies from 2022 to 2026. Finally, we take up the recent proposal by ESM economists to increase the permissible debt ratio from 60 to 100% of GDP in the eurozone.
Metabolic adaptation and signal integration in response to hypoxic conditions is mainly regulated by hypoxia-inducible factors (HIFs). At the same time, hypoxia induces ROS formation and activates the unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress. However, whether ER stress would affect the hypoxia response remains ill-defined. Here we report that feeding mice a high fat diet causes ER stress and attenuates the response to hypoxia. Mechanistically, ER stress promotes HIF-1α and HIF-2α degradation independent of ROS, Ca2+, and the von Hippel-Lindau (VHL) pathway, involving GSK3β and the ubiquitin ligase FBXW1A/βTrCP. Thereby, we reveal a previously unknown function of the GSK3β/HIFα/βTrCP1 axis in ER homeostasis and demonstrate that inhibition of the HIF-1 and HIF-2 response and genetic deficiency of GSK3β affects proliferation, migration, and sensitizes cells for ER stress promoted apoptosis. Vice versa, we show that hypoxia affects the ER stress response mainly through the PERK-arm of the UPR. Overall, we discovered previously unrecognized links between the HIF pathway and the ER stress response and uncovered an essential survival pathway for cells under ER stress.