Prediction of cardiac worsening through to cardiogenic shock in patients with acute heart failure

Aims: Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new‐onset CS in patients hospitalized for AHF. Methods and results: Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow‐up until death or discharge. WHF was defined by the RELAX‐AHF‐2 criteria. CS was defined as SCAI stages B–E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In‐hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21–36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32–231.81, P < 0.001). Chronic kidney disease (OR 2.20, 95% CI 1.25–3.93, P = 0.007), logarithmized serum creatinine (OR 2.90, 95% CI 1.51–5.82, P = 0.002), cystatin c (OR 1.86, 95% CI 1.27–2.77, P = 0.002), tricuspid valve regurgitation (OR 2.08, 95% CI 1.11–3.94, P = 0.023) and logarithmized pro‐adrenomedullin (OR 3.01, 95% CI 1.75–5.38, P < 0.001) were significant predictors of WHF. Chronic kidney disease (OR 3.17, 95% CI 1.16–9.58, P = 0.03), cystatin c (OR 1.88, 95% CI 1.00–3.53, P = 0.045), logarithmized pro‐adrenomedullin (OR 2.90, 95% CI 1.19–7.19, P = 0.019), and tricuspid valve regurgitation (OR 10.44, 95% CI 2.61–70.00, P = 0.003) were significantly with new‐onset CS. Conclusions: Half of patients admitted with AHF experience WHF or new‐onset CS. Chronic kidney disease, tricuspid valve regurgitation, and elevated pro‐adrenomedullin concentrations predict these events. They could potentially serve as early warning signs for further deterioration in AHF patients

Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock

Background: Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS. Methods: Unselected, consecutive patients with CS and CRP measurements treated at a single large cardiovascular center between 2009 and 2019 were analyzed. Adjusted regression models were fitted to evaluate the association of CRP with shock severity, 30-day in-hospital mortality and treatment response to MCS. Results: The analysis included 1116 patients [median age: 70 (IQR 58–79) years, 795 (71.3%) male, lactate 4.6 (IQR 2.2–9.5) mmol/l, CRP 17 (IQR 5–71) mg/l]. The cause of CS was acute myocardial infarction in 530 (48%) patients, 648 (58%) patients presented with cardiac arrest. Plasma CRP concentrations were equally distributed across shock severities (SCAI stage B–E). Higher CRP concentrations were associated with 30-day in-hospital mortality (8% relative risk increase per 50 mg/l increase in CRP, range 3–13%; p < 0.001), even after adjustment for CS severity and other potential confounders. Higher CRP concentrations were only associated with higher mortality in patients not treated with MCS [hazard ratio (HR) for CRP > median 1.50; 95%-CI 1.21–1.86; p < 0.001], but not in those treated with MCS (HR for CRP > median 0.92; 95%-CI 0.67–1.26; p = 0.59; p-interaction = 0.01). Conclusion: Elevated CRP concentrations are associated with increased 30-day in-hospital mortality in unselected patients with cardiogenic shock. The use of mechanical circulatory support attenuates this association

Effects of pharmacological inhibition of the ULK1 kinase on acute axonal degeneration in vivo

Hintergrund: Die axonale Degeneration ist ein grundlegender Prozess in der Pathophysiologie traumatischer und neurodegenerativer Nervenerkrankungen des ZNS. In der akuten axonalen Degeneration folgt innerhalb der ersten Stunden nach lokaler Axonläsion ein progredienter Integritäts- und Funktionsverlust. Ein frühes molekulares Charakteristikum der akuten axonalen Degeneration ist die Aktivierung von Autophagie, die sich durch eine hochregulierte Expression von Autophagieproteinen wie Unc51-like-autophagy-activating-kinase (ULK1) zeigt und noch unvollstädnig verstanden ist. Fragestellung: Ziel der vorliegenden Studie war es, im translationalen Ansatz die Effekte einer therapeutischen ULK1-Inhibiton durch den ULK-1-Inhibitor SBI-0206965 auf die akute axonale Degeneration in vivo zu untersuchen. Methodik: Für die Analyse morphologischer Charakteristika der AAD wurden nach einer Crush-Läsion eine In-vivo-live-imaging-Mikroskopie durchgeführt. Für die Axonmarkierung wurde 14 Tage vor der Crush-Läsion AAV.EGFP intravitreal appliziert. Der Inhibitor SBI-0206965 (5 µM oder 50 µM) wurde 2,5 h vor der Crush-Läsion intravitreal injiziert und anschließend ein Live-Imaging im Bereich 400–500 µm proximal zur Läsionsstelle über 360 min durchgeführt. Die AAD wurde durch die Axonal integrity ratio und durch die Anaylse von axonalen Bulbs quantifiziert. Die Quantifizierung von LC3- und p62-Puncta im optischen Nerv 400 µm proximal und distal der Läsionsstelle erfolgte mittels Immunhistochemie und anschließender Konfokalmikroskopie. Ergebnisse: Die intravitreale Injektion von 50 μM SBI-0206965 führte zu einer signifikanten Reduktion der axonalen Fragmentierung vier und fünf Stunden nach Crush-Läsion. Hingegen zeigte die Konzentration von 5 μM SBI-0206965 keine Verringerung des axonalen Integritätsverlusts. Axonale Bulb-Strukturen blieben in Größe und Anzahl innerhalb von fünf Stunden nach der Läsionssetzung im Wesentlichen unbeeinflusst. Fünf Stunden nach Crush-Läsion verringerte 50 μM SBI-0206965 die Anzahl intraaxonaler LC3-positiver Puncta und erhöhte nachweislich die Anzahl p62-positver Puncta, was auf eine Hemmung der Autophagosomenbildung durch SBI hinweist. Konklusion: Im translationalen Ansatz wurden Effekte des ULK1-Inhibitor SBI-0206965 auf die AAD nach Crush-Läsion des optischen Nervs in vivo anaysiert. Zusammenfassend erstmalig ein protektiver Effekt auf die akute axonale Degeneration durch eine SBI-0206965 vermittelte Autophagieinhibition gezeigt werden. ULK1 könnte als wichtiger Mediator in axonalen Degenerationsprozessen ein neues therapeutisches Ziel bei traumatischen und neurodegenerativen Erkrankungen des zentralen Nervensystems darstellen, jedoch sind weitere Forschungsanstrengungen dringend nötig.Background: Axonal degeneration is a key and early pathological feature in neurodegenerative and traumatic disorders of the central nervous system. A focal lesion to an axon is followed by a rapid disintegration within several hours, named acute axonal degeneration (AAD). During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Objective: The aim of this study was to investigate the effects of therapeutic ULK1 inhibition by the small-molecule ULK-1 inhibitor SBI-0206965 on acute axonal degeneration in vivo in a translational approach. Methods: To evaluate AAD in vivo, rat optic nerve crush and live imaging were performed. Intravitreal injections of AAV.EGFP were administered 14 days before nerve crush to label the axons. SBI-0206965 (5 µM or 50 µM) was injected intravitreally 2.5 h prior to nerve crush. Z-stack images were taken in the area of 400–500 µm proximal to the crush site 5–360 min after crush, and AAD was quantified by axonal integrity ratio and axonal bulb analysis. Quantification of LC3- and p62-puncta in the optic nerve were performed with immunohistochemistry and confocal microscopy 400 µm proximal and distal to the crush lesion. Results: Treatment with 50 µM SBI-0206965 resulted in a significant reduction of axonal fragmentation as measured by the axonal integrity ratio compared to control starting 4 h after crush. In contrast, the concentration of 5 μM SBI-0206965 showed no reduction in axonal integrity loss. Axonal bulb structures remained essentially unaffected in size and number within five hours postlesion. Treatment with 50 μM SBI-0206965 significantly lowered the number of distal LC3 puncta and was shown to increase the number of p62 puncta, indicating the inhibition of autophagosome formation by SBI. Conclusion: In a translational approach, we tested whether application of the ULK1 inhibitor SBI-0206965 affects AAD after rat optic nerve crush in vivo. Taken together, our data demonstrate that SBI could inhibit autophagy and attenuate AAD after lesion in vivo. Thus, ULK1 could represent a novel therapeutic target in traumatic and degenerative diseases of the central nerve system, but further research efforts are urgently needed.2022-09-1