Background
Sepsis and inflammation can cause intensive care unit‐acquired weakness (ICUAW). Increased interleukin‐6 (IL‐6) plasma levels are a risk factor for ICUAW. IL‐6 signalling involves the ...glycoprotein 130 (gp130) receptor and the JAK/STAT‐pathway, but its role in sepsis‐induced muscle wasting is uncertain. In a clinical observational study, we found that the IL‐6 target gene, SOCS3, was increased in skeletal muscle of ICUAW patients indicative for JAK/STAT‐pathway activation. We tested the hypothesis that the IL‐6/gp130‐pathway mediates ICUAW muscle atrophy.
Methods
We sequenced RNA (RNAseq) from tibialis anterior (TA) muscle of cecal ligation and puncture‐operated (CLP) and sham‐operated wildtype (WT) mice. The effects of the IL‐6/gp130/JAK2/STAT3‐pathway were investigated by analysing the atrophy phenotype, gene expression, and protein contents of C2C12 myotubes. Mice lacking Il6st, encoding gp130, in myocytes (cKO) and WT controls, as well as mice treated with the JAK2 inhibitor AG490 or vehicle were exposed to CLP or sham surgery for 24 or 96 h.
Results
Analyses of differentially expressed genes in RNAseq (≥2‐log2‐fold change, P < 0.01) revealed an activation of IL‐6‐signalling and JAK/STAT‐signalling pathways in muscle of septic mice, which occurred after 24 h and lasted at least for 96 h during sepsis. IL‐6 treatment of C2C12 myotubes induced STAT3 phosphorylation (three‐fold, P < 0.01) and Socs3 mRNA expression (3.1‐fold, P < 0.01) and caused myotube atrophy. Knockdown of Il6st diminished IL‐6‐induced STAT3 phosphorylation (−30.0%; P < 0.01), Socs3 mRNA expression, and myotube atrophy. JAK2 (− 29.0%; P < 0.01) or STAT3 inhibition (−38.7%; P < 0.05) decreased IL‐6‐induced Socs3 mRNA expression. Treatment with either inhibitor attenuated myotube atrophy in response to IL‐6. CLP‐operated septic mice showed an increased STAT3 phosphorylation and Socs3 mRNA expression in TA muscle, which was reduced in septic Il6st‐cKO mice by 67.8% (P < 0.05) and 85.6% (P < 0.001), respectively. CLP caused a loss of TA muscle weight, which was attenuated in Il6st‐cKO mice (WT: −22.3%, P < 0.001, cKO: −13.5%, P < 0.001; WT vs. cKO P < 0.001). While loss of Il6st resulted in a reduction of MuRF1 protein contents, Atrogin‐1 remained unchanged between septic WT and cKO mice. mRNA expression of Trim63/MuRF1 and Fbxo32/Atrogin‐1 were unaltered between CLP‐treated WT and cKO mice. AG490 treatment reduced STAT3 phosphorylation (−22.2%, P < 0.05) and attenuated TA muscle atrophy in septic mice (29.6% relative reduction of muscle weight loss, P < 0.05). The reduction in muscle atrophy was accompanied by a reduction in Fbxo32/Atrogin‐1‐mRNA (−81.3%, P < 0.05) and Trim63/MuRF1‐mRNA expression (−77.6%, P < 0.05) and protein content.
Conclusions
IL‐6 via the gp130/JAK2/STAT3‐pathway mediates sepsis‐induced muscle atrophy possibly contributing to ICUAW.
Background Proctoring represents a cornerstone in the acquisition of state-of-the-art cardiovascular interventions. Yet, travel restrictions and containment measures during the COVID-19 pandemic ...limited on-site proctoring for training and expert support in interventional cardiology. Methods and Results We established a teleproctoring setup for training in a novel patent foramen ovale closure device system (NobleStitch EL, HeartStitch Inc, Fountain Valley, CA) at our institution using web-based real-time bidirectional audiovisual communication. A total of 6 patients with prior paradoxical embolic stroke and a right-to-left shunt of grade 2 or 3 were treated under remote proctorship after 3 cases were performed successfully under on-site proctorship. No major device/procedure-related adverse events occurred, and none of the patients had a residual right-to-left shunt of grade 1 or higher after the procedure. Additionally, we sought to provide an overview of current evidence available for teleproctoring in interventional cardiology. Literature review was performed identifying 6 previous reports on teleproctoring for cardiovascular interventions, most of which were related to the current COVID-19 pandemic. In all reports, teleproctoring was carried out in similar settings with comparable setups; no major adverse events were reported. Conclusions Teleproctoring may represent a feasible and safe tool for location-independent and cost-effective training in a novel patent foramen ovale closure device system. Future prospective trials comparing teleproctoring with traditional on-site proctoring are warranted.
The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that ...often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice. Mice were subjected to transverse aortic constriction (TAC, 27G; AAV9-Luc:
= 9; AAV9-Tfeb:
= 14) or sham (AAV9-Luc:
= 9; AAV9-Tfeb:
= 9) surgery for 28 days. Heart morphology, echocardiography, gene expression, and protein levels were monitored. AAV9-Tfeb had no effect on cardiac structure and function in sham animals. TAC resulted in compensated left ventricular hypertrophy in AAV9-Luc mice. AAV9-Tfeb TAC mice showed a reduced LV ejection fraction and increased left ventricular diameters. Morphological, histological, and real-time PCR analyses showed increased heart weights, exaggerated fibrosis, and higher expression of stress markers and remodeling genes in AAV9-Tfeb TAC compared to AAV9-Luc TAC. RNA-sequencing, real-time PCR and Western Blot revealed a stronger ALP activation in the hearts of AAV9-Tfeb TAC mice. Cardiomyocyte-specific TFEB-overexpression promoted ALP gene expression during TAC, which was associated with heart failure. Treatment of ALP-related diseases by overexpression of TFEB warrants careful consideration.
Randomized trials suggest benefits for fractional flow reserve (FFR)-guided vs. angiography-guided treatment strategies in well-defined and selected patient cohorts with acute coronary syndromes ...(ACS). The long-term prognostic value of FFR measurement in unselected all-comer ACS patients, however, remains unknown. This subanalysis of the Fractional FLOw Reserve In cardiovascular DiseAses (FLORIDA) study sought to investigate the long-term effects of FFR in the management of lesions in patients with acute coronary syndrome (ACS). FLORIDA was an observational all-comer cohort study performed in Germany, that was population-based and unselected. Patients enrolled into the anonymized InGef Research Database presenting with ACS and undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Patients were stratified into either the FFR-guided or the angiography-guided treatment arm, based on the treatment received. A matched cohort study design was used. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), a composite of death, non-fatal myocardial infarction (MI), and repeat revascularization. Follow-up time was 3 years. Rates of 3-year mortality were 10.2 and 14.0% in the FFR-guided and the angiography-guided treatment arms (
p
= 0.04), corresponding to a 27% relative risk reduction for FFR in ACS patients. Rates of MACE were similar in both arms (47.7 vs. 51.5%,
p
= 0.14), including similar rates of non-fatal MI (27.7 vs. 25.4%,
p
= 0.47) and revascularization (9.9 vs. 12.1%,
p
= 0.17). In this large, all-comer observational study of ACS patients, FFR-guided revascularization was associated with a lower mortality at 3 years. This finding encourages the routine use of FFR to guide lesion revascularization in patients presenting with ACS.
Abstract only
Introduction:
The senescence-associated secretory phenotype (SASP) is a potential driver of age-related risk reflecting advanced biological aging. Circulating SASP components include ...pro-inflammatory cytokines, growth modulators and matrix remodelling proteases. Aortic valve stenosis (AVS) is the prototypical inflammatory age-associated cardiovascular disease.
Hypothesis:
To identify circulating SASP components with an impact on prognosis in elderly pts with AVS.
Methods:
In a derivation cohort (n=120), circulating levels of 24 SASP components were measured using Luminex Multiplex ELISA, before undergoing TAVR. ROC curves and Youden-index derived optimal cut-off values were used to assess the predictive power of each SASP for long-term mortality. In a validation cohort (n=198), the significant predictors of mortality identified in the derivation cohort, as well as a panel of 3 independent predictors in multivariate analyses, were prospectively validated.
Results:
In the derivation cohort, 9 out of 24 SASP components significantly predicted mortality in univariate analyses with AUC>0.62; only 3 (GDF-15, ICAM-1, and osteoprotegerin) remained independent predictors in multivariate analyses (all p<0.03). All 3 were confirmed as significant independent predictors of mortality in the validation cohort (see AUC curves). After adjustment for clinical parameters, a score based on the cumulative number of these 3 SASP components showed a substantial increase in long-term mortality after TAVR for each additional positive marker (see KM-curves).
Conclusions:
This study validates high levels of 3 SASP components reflecting different pathophysiological pathways of senescence as independent predictors of long-term mortality in AVS. Their cumulative occurrence provides a deeply improved discrimination power and, may serve as a much needed risk stratification tool in elderly patients with AVS undergoing TAVR.
Abstract only Background: Aortic valve stenosis (AVS) is an age-related disease lacking effective causal therapies. Aging is linked to cellular senescence, which leads to the secretion of the ...“senescence-associated secretory phenotype” (SASP). Recent evidence suggests a connection between AVS and SASP expression. Aim: The study aimed to assess expression patterns and the prognostic impact of SASP components in patients undergoing transcatheter valve replacement (TAVR) for severe AVS. Methods: We analyzed 12 SASP components in plasma from 320 patients undergoing TAVR between February 2017 and September 2021, using the Luminex® Assay (Bio-Techne, Germany). Follow-Up was conducted up to 3 years after TAVR with all-cause mortality as the primary endpoint. Hierarchical clustering was performed to identify patterns of SASP expression, and clusters were analyzed for their impact on survival, associations with age and frailty of patients. Significant covariates (p<0.1), as identified by univariate regression, were included in the AFT model for survival analyses. Results: The patients’ median age was 83.2 years (95%CI 82.4 - 83.9), with 39.7% being female. Hierarchical clustering revealed 3 main clusters, characterized by circulating concentrations of pro-inflammatory cytokines (Fig. A). Clusters with higher levels of pro-inflammatory SASP components showed worse survival after adjusting for covariates (COPD, previous stroke, NYHA class, eGFR, anemia) (Fig. B). Patients’ age did not differ between clusters, but those in clusters with higher levels of pro-inflammatory markers were more likely to be frail (Fig. C). Conclusion: In elderly patients undergoing TAVR for severe AVS, pro-inflammatory SASP components are associated with worse survival, independent of chronologic age. These findings suggest a role of cellular senescence and markers of ‘inflammaging’ in outcomes of patients with AVS and might also enhance risk stratification in patients with AVS undergoing TAVR.
Abstract
Aims
Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical ...outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients.
Methods and results
This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years major adverse cardiovascular events (MACE+). Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1β. Circulating plasma levels of interleukin-1β decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+.
Conclusion
This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials.
Structured Graphical Abstract
Structured Graphical Abstract
ACS, acute coronary syndrome; IFC, intact fibrous cap; IL-6, interleukin-6; LDLC, low-density lipoprotein cholesterol; MACE+, major adverse cardiovascular events, MΦ, macrophage; RFC, ruptured fibrous cap; TCFA, thin-cap fibro-atheroma. ns, not significant; *P < 0.05.
Spotty calcium deposits (SCD) represent a vulnerable plaque feature which seems to result - as based on recent invitro studies - from inflammatory vessel-wall interactions. SCD can be reliably ...assessed by optical coherence tomography (OCT). Their prognostic impact is yet unknown. Therefore, the aims of this translational study were to comprehensively characterize different plaque calcification patterns, to analyze the associated inflammatory mechanisms in the microenvironment of acute coronary syndrome (ACS)-causing culprit lesions (CL) and to investigate the prognostic significance of SCD in a large cohort of ACS-patients.
CL of the first 155 consecutive ACS-patients from the translational OPTICO-ACS-study program were investigated by OCT-characterization of the calcium phenotype at ACS-causing culprit lesions. Simultaneous immunophenotyping by flow-cytometric analysis and cytokine bead array technique across the CL gradient (ratio local/systemic levels) was performed and incidental major adverse cardiovascular events plus (MACE+) at 12 months after ACS were assessed.
SCD were observed within 45.2% of all analyzed ACS-causing culprit lesions (CL). Culprits containing spotty calcium were characterized by an increased culprit ratio of innate effector cytokines interleukin (IL)-8 2.04 (1.24) vs. 1.37 (1.10) p < 0.05, as well as TNF (tumor necrosis factor)-α 1.17 (0.93) vs. 1.06 (0.89); p < 0.05) and an increased ratio of circulating neutrophils 0.96 (0.85) vs. 0.91 (0.77); p < 0.05 as compared to culprit plaques without SCD. Total monocyte levels did not differ between the two groups (p = n.s.). However, SCD-containing CLs were characterized by an increased culprit ratio of intermediate monocytes (1.15 (0.81) vs. 0.96 (0.84); p < 0.05) with an enhanced surface expression of the integrin receptor CD49d as compared to intermediate monocytes derived from SCD-free CLs (1.06 (0.94) vs. 0.97 (0.91) p < 0.05. Finally, 12 months rates of MACE+ were higher in patients with, as compared to patients without SCD at CL (16.4% vs. 5.3%; p < 0.05).
This study for the first time identified a specific inflammatory profile of CL with SCD, with a predominance of neutrophils, intermediate monocytes and their corresponding effector molecules. Hence, this study advances our understanding of ACS-causing CL and provides the basis for future personalized anti-inflammatory, therapeutic approaches to ACS.
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•Spotty calcium deposits (SCD) represent a feature of plaque vulnerability.•SCD are associated with a distinct, pro-inflammatory micro-environment at acute coronary syndrome (ACS)-causing culprit lesions.•SCD are associated with increased cardiovascular event rates at one-year follow up.•SCD may thereby facilitate secondary prevention and advance anti-inflammatory therapy after ACS.
Owing to the limited availability of suitable precursors for vapor phase deposition of rare‐earth containing thin‐film materials, new or improved precursors are sought after. In this study, we ...explored new precursors for atomic layer deposition (ALD) of cerium (Ce) and ytterbium (Yb) containing thin films. A series of homoleptic tris‐guanidinate and tris‐amidinate complexes of cerium (Ce) and ytterbium (Yb) were synthesized and thoroughly characterized. The C‐substituents on the N‐C‐N backbone (Me, NMe2, NEt2, where Me=methyl, Et=ethyl) and the N‐substituents from symmetrical iso‐propyl (iPr) to asymmetrical tertiary‐butyl (tBu) and Et were systematically varied to study the influence of the substituents on the physicochemical properties of the resulting compounds. Single crystal structures of Ce(dpdmg)3 1 and Yb(dpdmg)3 6 (dpdmg=N,N'‐diisopropyl‐2‐dimethylamido‐guanidinate) highlight a monomeric nature in the solid‐state with a distorted trigonal prismatic geometry. The thermogravimetric analysis shows that the complexes are volatile and emphasize that increasing asymmetry in the complexes lowers their melting points while reducing their thermal stability. Density functional theory (DFT) was used to study the reactivity of amidinates and guanidinates of Ce and Yb complexes towards oxygen (O2) and water (H2O). Signified by the DFT calculations, the guanidinates show an increased reactivity toward water compared to the amidinate complexes. Furthermore, the Ce complexes are more reactive compared to the Yb complexes, indicating even a reactivity towards oxygen potentially exploitable for ALD purposes. As a representative precursor, the highly reactive Ce(dpdmg)3 1 was used for proof‐of‐principle ALD depositions of CeO2 thin films using water as co‐reactant. The self‐limited ALD growth process could be confirmed at 160 °C with polycrystalline cubic CeO2 films formed on Si(100) substrates. This study confirms that moving towards nitrogen‐coordinated rare‐earth complexes bearing the guanidinate and amidinate ligands can indeed be very appealing in terms of new precursors for ALD of rare earth based materials.
Systematic engineering of Ce and Yb based amidinate and guanidinate complexes resulted in precursors suitable for atomic layer deposition (ALD) applications. Computational modeling reveals the reactivity of the complexes towards water and oxygen. A water assisted ALD process for the growth of CeO2 thin films was demonstrated with the Ce tris‐guanidinate precursor.
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