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Extracorporeal life support systems (ECLS) are life-sustaining measures for severe cardiovascular diseases, serving as bridging treatment either until cardiovascular function is restored or alternative treatment, such as heart transplantation or the implantation of permanent ventricular assist devices is performed. Given the insufficient evidence and frequent urgency of implantation without initial patient consent, the ethical challenges and psychological burden for patients, relatives and the interprofessional intensive care team are significant. As with any treatment, an appropriate therapeutic goal for ECLS treatment based on the indications and patient informed consent is mandatory. In order to integrate the necessary ethical considerations into everyday clinical practice, a structured algorithm for handling ECLS is proposed here, which takes ethical aspects into due account., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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Background: In Europe, more than 300,000 persons per year experience out-of-hospital cardiac arrest (OHCA). Despite medical progress, only few patients survive with good neurological outcome. For many issues, evidence from randomized trials is scarce. OHCA often occurs for cardiac causes. Therefore, we established the national, prospective, multicentre German Cardiac Arrest Registry (G-CAR). Herein, we describe the first results of the pilot phase., Results: Over a period of 16 months, 15 centres included 559 consecutive OHCA patients aged ≥ 18 years. The median age of the patients was 66 years (interquartile range 57;75). Layperson resuscitation was performed in 60.5% of all OHCA cases which were not observed by emergency medical services. The initial rhythm was shockable in 46.4%, and 29.1% of patients had ongoing CPR on hospital admission. Main presumed causes of OHCA were acute coronary syndromes (ACS) and/or cardiogenic shock in 54.8%, with ST-elevation myocardial infarction being the most common aetiology (34.6%). In total, 62.9% of the patients underwent coronary angiography; percutaneous coronary intervention (PCI) was performed in 61.4%. Targeted temperature management was performed in 44.5%. Overall in-hospital mortality was 70.5%, with anoxic brain damage being the main presumed cause of death (38.8%). Extracorporeal cardiopulmonary resuscitation (eCPR) was performed in 11.0%. In these patients, the in-hospital mortality rate was 85.2%., Conclusions: G-CAR is a multicentre German registry for adult OHCA patients with a focus on cardiac and interventional treatment aspects. The results of the 16-month pilot phase are shown herein. In parallel with further analyses, scaling up of G-CAR to a national level is envisaged. Trial registration ClinicalTrials.gov identifier: NCT05142124., (© 2024. The Author(s).)

Background: High blood pressure is a major risk factor for cardiac remodeling and left ventricular hypertrophy, increasing cardiovascular risk and leading to heart failure with preserved ejection fraction (HFpEF). Since renal sympathetic denervation (RDN) reduces blood pressure in the long term, we aimed to investigate the long-term effect of RDN in patients with HFpEF in the present analysis., Methods: Patients previously enrolled in a local RDN registry who underwent high-frequency RDN with the use of the Symplicity Flex® renal denervation system between 2011 and 2014 were followed up. The patients were assessed by 24-h ambulatory blood pressure measurement, transthoracic echocardiography, and laboratory tests. We used the echocardiographic and biomarker criteria of the Heart Failure Association (HFA)-PEFF (Pre-test assessment, Echocardiography and Natriuretic Peptide Score, Funkctional testing, and Final aetiology) score to identify patients with HFpEF., Results: Echocardiographic assessment was available for 70 patients at a 9-year long-term follow-up. Of these patients, 21 had HFpEF according to the HFA-PEFF score. We found a significant reduction of the HFA-PEFF score from 5.48 ± 0.51 points at baseline to 4.33 ± 1.53 points at the 9-year follow-up ( P  < 0.01). This decrease was due to a greater reduction in morphological and biomarker subcategories [from 1.95 ± 0.22 to 1.43 ± 0.51 points ( P  < 0.01) and from 1.52 ± 0.52 to 0.90 ± 0.63 points ( P  < 0.01), respectively] than in the functional one. Morphologically, there was a reduction in left ventricular hypertrophy and left atrial dilation., Conclusions: The present analysis suggests that RDN may lead to a regression of the extent of HFpEF beyond a reduction in blood pressure and thus possibly contribute to an improvement in prognosis. More detailed information will be provided by ongoing randomized sham-controlled trials., Competing Interests: AV and AP received consulting fees from Medtronic. AP was a proctor for Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Vogt, Plehn, Atti, Nussbaum, Tongers, Sedding and Dutzmann.)

Background: Intermittent fasting has shown positive effects on numerous cardiovascular risk factors. The INTERFAST-MI trial (Intermittent Fasting in Myocardial Infarction) has been designed to study the effects of intermittent fasting on cardiac function after STEM (ST-segment-elevation myocardial infarction) and the feasibility of future multicenter trials., Methods: The INTERFAST-MI study was a prospective, randomized, controlled, nonblinded, single-center investigator-initiated trial. From October 1, 2020, to July 15, 2022, 48 patients were randomized to the study groups intermittent fasting or regular diet and followed for 6 months with follow-up visits at 4 weeks and 3 months., Results: In all, 22 of 24 patients in the intermittent fasting group with a mean age of 58.54±12.29 years and 20 of 24 patients in the regular diet group with a mean age of 59.60±13.11 years were included in the intention-to-treat population. The primary efficacy end point (improvement in left ventricular ejection fraction after 4 weeks) was significantly greater in the intermittent fasting group compared with the control group (mean±SD, 6.636±7.122%. versus 1.450±4.828%; P =0.038). This effect was still significant and even more pronounced after 3 and 6 months. The patients in the intermittent fasting group showed a greater reduction in diastolic blood pressure and body weight compared with the control group. The mean adherence of patients in the intermittent fasting group was a median of 83.7% (interquartile range, 69.0%-98.4%) of all days. None of the patients from either group reported dizziness, syncope, or collapse., Conclusions: Our results suggest that intermittent fasting after myocardial infarction may be safe and could improve left ventricular function after STEMI., Registration: URL: https://www.drks.de; Unique identifier: DRKS00021784., Competing Interests: Disclosures None.

The rise in intensive care treatment procedures is accompanied by an increase in the complexity of decisions regarding the selection, administration and duration of treatment measures. Whether a treatment goal is desirable in an individual case and the treatment plan required to achieve it is acceptable for the patient depends on the patient's preferences, values and life plans. There is often uncertainty as to whether a patient-centered treatment goal can be achieved. The use of a time-limited treatment trial (TLT) as a binding agreement between the intensive care unit (ICU) team and the patient or their legal representative on a treatment concept over a defined period of time in the ICU can be helpful to reduce uncertainties and to ensure the continuation of intensive care measures in the patients' best interest., (© 2024. The Author(s).)

Circulating endothelial cells (CEC) are arising as biomarkers for vascular diseases. However, whether they can be utilized as markers of endothelial cell (EC) senescence in vivo remains unknown. Here, we present a protocol to isolate circulating endothelial cells for a characterization of their senescent signature. Further, we characterize different models of EC senescence induction in vitro and show similar patterns of senescence being upregulated in CECs of aged patients as compared to young volunteers. Replication-(ageing), etoposide-(DNA damage) and angiotensin II-(ROS) induced senescence models showed the expected cell morphology and proliferation-reduction effects. Expression of senescence-associated secretory phenotype markers was specifically upregulated in replication-induced EC senescence. All models showed reduced telomere lengths and induction of the INK4a/ARF locus. Additional p14ARF-p21 pathway activation was observed in replication- and etoposide-induced EC senescence. Next, we established a combined magnetic activated- and fluorescence activated cell sorting (MACS-FACS) based protocol for CEC isolation. Interestingly, CECs isolated from aged volunteers showed similar senescence marker patterns as replication- and etoposide-induced senescence models. Here, we provide first proof of senescence in human blood derived circulating endothelial cells. These results hint towards an exciting future of using CECs as mirror cells for in vivo endothelial cell senescence, of particular interest in the context of endothelial dysfunction and cardiovascular diseases., (© 2024. The Author(s).)

The rapid development of safe and effective vaccines helped to prevent severe disease courses after SARS-CoV-2 infection and to mitigate the progression of the COVID-19 pandemic. While there is evidence that vaccination may reduce the risk of developing post-COVID-19 conditions (PCC), this effect may depend on the viral variant. Therapeutic effects of post-infection vaccination have been discussed but the data for individuals with PCC remains inconclusive. In addition, extremely rare side effects after SARS-CoV-2 vaccination may resemble the heterogeneous PCC phenotype. Here, we analyze the plasma levels of 25 cytokines and SARS-CoV-2 directed antibodies in 540 individuals with or without PCC relative to one or two mRNA-based COVID-19 vaccinations as well as in 20 uninfected individuals one month after their initial mRNA-based COVID-19 vaccination. While none of the SARS-CoV-2 naïve individuals reported any persisting sequelae or exhibited PCC-like dysregulation of plasma cytokines, we detected lower levels of IL-1β and IL-18 in patients with ongoing PCC who received one or two vaccinations at a median of six months after infection as compared to unvaccinated PCC patients. This reduction correlated with less frequent reporting of persisting gastrointestinal symptoms. These data suggest that post-infection vaccination in patients with PCC might be beneficial in a subgroup of individuals displaying gastrointestinal symptoms., (© 2024. The Author(s).)

The process recommendations of the Ethics Section of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) for ethically based decision-making in intensive care medicine are intended to create the framework for a structured procedure for seriously ill patients in intensive care. The processes require appropriate structures, e.g., for effective communication within the treatment team, with patients and relatives, legal representatives, as well as the availability of palliative medical expertise, ethical advisory committees and integrated psychosocial and spiritual care services. If the necessary competences and structures are not available in a facility, they can be consulted externally or by telemedicine if necessary. The present recommendations are based on an expert consensus and are not the result of a systematic review or a meta-analysis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

In recent years, the number of intensive care treatments has increased significantly. About every fourth patient who dies in hospital receives intensive care. Structured prevention planning is important in order to implement the patient's wishes in situations of serious illness in which patients cannot express their wishes themselves. However, the implementation in practice can be problematic since intensive care situations are complex and rarely correspond to the concrete pre-arranged situations. Communication of the prognosis and the prognostic uncertainty is therefore crucial in order to determine the presumed will of the patient, especially in the context of the process of weighing up the benefits and burdens of intensive care therapies. Hospital treatment can be the reason for targeted preventive planning and avoid unnecessary intensive care treatment during the same stay. Documentation templates can help to record the results of preventive care planning clearly and comprehensibly in the medical file., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Renal sympathetic denervation (RDN) has been shown to lower arterial blood pressure both in the presence and in the absence of antihypertensive medication in an observation period of up to 3 years. However, long-term results beyond 3 years are scarcely reported., Methods: We performed a long-term follow-up on patients who were previously enrolled in a local renal denervation registry and who underwent radiofrequency RDN with the Symplicity Flex® renal denervation system between 2011 and 2014. The patients were assessed to evaluate their renal function by performing 24-hour ambulatory blood pressure measurement (ABPM), recording their medical history, and conducting laboratory tests., Results: Ambulatory blood pressure readings for 24 h were available for 72 patients at long-term follow-up (FU) [9.3 years (IQR: 8.5-10.1)]. We found a significant reduction of ABP from 150.1/86.1 ± 16.9/12.0 mmHg at baseline to 138.3/77.1 ± 16.5/11.1 mmHg at long-term FU ( P  < 0.001 for both systolic and diastolic ABP). The number of antihypertensive medications used by the patients significantly decreased from 5.4 ± 1.5 at baseline to 4.8 ± 1.6 at long-term FU ( P  < 0.01). Renal function showed a significant but expected age-associated decrease in the eGFR from 87.8 (IQR: 81.0-100.0) to 72.5 (IQR: 55.8-86.8) ml/min/1.73 m 2 ( P  < 0.01) in patients with an initial eGFR > 60 ml/min/1.73 m 2 , while a non-significant decrease was observed in patients with an initial eGFR < 60 ml/min/1.73 m 2 at long-term FU [56.0 (IQR: 40.9-58.4) vs. 39.0 (IQR: 13.5-56.3) ml/min/1.73 m 2 ]., Conclusions: RDN was accompanied by a long-lasting reduction in blood pressure with a concomitant reduction in antihypertensive medication. No negative effects could be detected, especially with regard to renal function., Competing Interests: AV and AP received consulting fees from Medtronic. AP was a proctor for Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Vogt, Dutzmann, Nußbaum, Hoyer, Tongers, Schlitt, Sedding and Plehn.)

Background: In Germany, 70,000-100,000 persons per year suffer from out-of-hospital cardiac arrest (OHCA). Despite medical progress, survival rates with good neurological outcome remain low. For many important clinical issues, no or only insufficient evidence from randomised trials is available. Therefore, a systemic and standardised acquisition of the treatment course and of the outcome of OHCA patients is warranted., Study Design: The German Cardiac Arrest Registry (G-CAR) is an observational, prospective, multicentre registry. It will determine the characteristics, initial treatment strategies, invasive procedures, revascularisation therapies and the use of mechanical circulatory support devices with a focus on extracorporeal cardiopulmonary resuscitation. A special feature is the prospective 12-month follow-up evaluating mortality, neurological outcomes and several patient-reported outcomes in the psychosocial domain (health-related quality of life, cognitive impairment, depression/anxiety, post-traumatic stress disorder and social reintegration). In a pilot phase of 24 months, 15 centres will include approximately 400 consecutive OHCA patients ≥ 18 years. Parallel to and after the pilot phase, scaling up of G-CAR to a national level is envisaged., Conclusion: G-CAR is the first national registry including a long-term follow-up for adult OHCA patients. Primary aim is a better understanding of the determinants of acute and long-term outcomes with the perspective of an optimised treatment., Trial Registry: NCT05142124. German Cardiac Arrest Registry (G-CAR)., (© 2022. The Author(s).)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Decisions with considerable medical and ethical implications are made in emergency departments every day. Despite time pressure and high workloads, they have to be arrived at in an expert manner in all dimensions. For immediate ethical decisions, structuring the decision-making process in the form of standard procedures can be helpful, provided that they are trained and practiced in an interdisciplinary and interprofessional manner. The support for ad hoc ethical decisions presented here recommends an "ethical team time out" for the evaluation of treatment choices, in a framework where the patient's will and medical indication are examined and completed in a structured manner. Further experts (ideally, an ad hoc clinical ethics consultation) should be consulted if the treatment measure is of questionable medical benefit and/or of questionable patient consent., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair the quality of life. Underlying mechanisms ranging from persistent viruses to innate and adaptive immune dysregulation have been discussed. Here, we profiled the plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero), including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as a potential biomarker for persistent viral reservoirs. At a median time of 8 months after infection, we found pronounced dysregulation in almost all tested soluble factors, including both pro-inflammatory and pro-fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC-specific patterns involving CCL2/MCP-1 and IL-8 that either correlated with sCD162, sCD206/MMR, IFN-α2, IL-17A and IL-33, or IL-18 and IL-23. None of the analyzed factors correlated with the detectability or levels of circulating S1, indicating that this represents an independent subset of patients with PASC. These data confirm prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrate its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Empagliflozin, an inhibitor of the sodium glucose co-transporter 2 (SGLT2) and developed as an anti-diabetic agent exerts additional beneficial effects on heart failure outcomes. However, the effect of empagliflozin on vascular cell function and vascular remodeling processes remains largely elusive., Methods/results: Immunocytochemistry and immunoblotting revealed SGLT2 to be expressed in human smooth muscle (SMC) and endothelial cells (EC) as well as in murine femoral arteries. In vitro , empagliflozin reduced serum-induced proliferation and migration of human diabetic and non-diabetic SMCs in a dose-dependent manner. In contrast, empagliflozin significantly increased the cell count and migration capacity of human diabetic ECs, but not of human non-diabetic ECs. In vivo , application of empagliflozin resulted in a reduced number of proliferating neointimal cells in response to femoral artery wire-injury in C57BL/6J mice and prevented neointima formation. Comparable effects were observed in a streptozocin-induced diabetic model of apolipoprotein E -/- mice. Conclusive to the in vitro -results, re-endothelialization was not significantly affected in C57BL/6 mice, but improved in diabetic mice after treatment with empagliflozin assessed by Evan's Blue staining 3 days after electric denudation of the carotid artery. Ribonucleic acid (RNA) sequencing (RNA-seq) of human SMCs identified the vasoactive peptide apelin to be decisively regulated in response to empagliflozin treatment. Recombinant apelin mimicked the in vitro -effects of empagliflozin in ECs and SMCs., Conclusion: Empagliflozin significantly reduces serum-induced proliferation and migration of SMCs in vitro and prevents neointima formation in vivo , while augmenting EC proliferation in vitro and re-endothelialization in vivo after vascular injury. These data document the functional impact of empagliflozin on vascular human SMCs and ECs and vascular remodeling in mice for the first time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dutzmann, Bode, Kalies, Korte, Knöpp, Kloss, Sirisko, Pilowski, Koch, Schenk, Daniel, Bauersachs and Sedding.)

Post-acute sequelae of COVID-19 (PASC) is emerging as global problem with unknown molecular drivers. Using a digital epidemiology approach, we recruited 8,077 individuals to the cohort study for digital health research in Germany (DigiHero) to respond to a basic questionnaire followed by a PASC-focused survey and blood sampling. We report the first 318 participants, the majority thereof after mild infections. Of those, 67.8% report PASC, predominantly consisting of fatigue, dyspnea, and concentration deficit, which persists in 60% over the mean 8-month follow-up period and resolves independently of post-infection vaccination. PASC is not associated with autoantibodies, but with elevated IL-1β, IL-6, and TNF plasma levels, which we confirm in a validation cohort with 333 additional participants and a longer time from infection of 10 months. Blood profiling and single-cell data from early infection suggest the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The treatment situation in intensive care is characterised by a specific asymmetry in the relationship between patients and the team: Patients are particularly dependent on their environment and often show impaired consciousness and capacity to consent. This facilitates the use of coercion or enables and/or provokes it. The aim of this recommendation is to show ways to recognise patients with their wishes and needs and to integrate them into treatment concepts in the intensive care unit in order to reduce and avoid coercion whenever possible. The recommendation shows the variety of possible forms of coercion and discusses the moral standards to be considered in the ethical weighing process as well as legal conditions for justifying its use. It becomes obvious that treatment measures which may involve the use of coercion always require a careful and self-critical review of the measures in relation to the indication and the therapeutic goal. The recommendation's intention therefore is not to disapprove the use of coercion by interprofessional teams. Instead, it aims to contribute to a sensitive perception of coercion and to a critical and caring approach to formal and especially informal (indirect) coercion., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Preclinical studies consistently show robust disease-modifying effects of intermittent fasting in animal models of cardiovascular disease. However, the impact of intermittent fasting on cardiovascular endpoints after myocardial infarction has not been investigated in a clinical trial so far., Methods and Analysis: The INTERmittent FASTing after Myocardial Infarction (INTERFAST-MI) trial is a monocentric prospective randomised controlled non-confirmatory pilot study including 48 patients with ST-segment elevation myocardial infarction. They will be randomised in a 1:1 ratio to either intermittent fasting (daily time-restricted eating; consuming food for not more than 8 hours/day, fasting for at least 16 hours/day) or to a control group without a particular diet. The follow-up time is 6 months. The prespecified primary outcome is change in left ventricular systolic function at 4 weeks from baseline to estimate effect size required to establishing sample size and power calculation for a future full-scale trial. Secondary outcomes include protocol adherence, recruitment, major adverse cardiac events, revascularisation, changes in left ventricular systolic function at 3 and 6 months, patient weight, blood pressure, and serum markers of inflammation and cardiovascular disease. Enrolment began on 1 November 2020 and is expected to conclude in December 2021., Ethics and Dissemination: The trial has received ethics approval from the Medical Ethics Committee of the Martin-Luther-University Halle-Wittenberg. Results of the study will be submitted for publication in a peer-reviewed journal and presented at scientific conferences., Trial Registration Number: DRKS00021784., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In parasite and viral infections, aberrant B cell responses can suppress germinal center reactions thereby blunting long-lived memory and may provoke immunopathology including autoimmunity. Using COVID-19 as model, we set out to identify serological, cellular, and transcriptomic imprints of pathological responses linked to autoreactive B cells at single-cell resolution. We show that excessive plasmablast expansions are prognostically adverse and correlate with autoantibody production but do not hinder the formation of neutralizing antibodies. Although plasmablasts followed interleukin-4 (IL-4) and BAFF-driven developmental trajectories, were polyclonal, and not enriched in autoreactive B cells, we identified two memory populations (CD80 + /ISG15 + and CD11c + /SOX5 + /T-bet +/- ) with immunogenetic and transcriptional signs of autoreactivity that may be the cellular source of autoantibodies in COVID-19 and that may persist beyond recovery. Immunomodulatory interventions discouraging such adverse responses may be useful in selected patients to shift the balance from autoreactivity toward long-term memory., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Objective: The explicit prohibition of discontinuing intensive care unit (ICU) treatment that has already begun by the newly established German Triage Act in favor of new patients with better prognoses (tertiary triage) under crisis conditions may prevent saving as many patients as possible and therefore may violate the international well-accepted premise of undertaking the "best for the most" patients. During the COVID-19 pandemic, authorities set up lockdown measures and infection-prevention strategies to avoid an overburdened health-care system. In cases of situational overload of ICU resources, when transporting options are exhausted, the question of a tertiary triage of patients arises., Methods: We provide data-driven analyses of score- and non-score-based tertiary triage policies using simulation and real-world electronic health record data in a COVID-19 setting. Ten different triage policies, for example, based on the Simplified Acute Physiology Score (SAPS II), are compared based on the resulting mortality in the ICU and inferential statistics., Results: Our study shows that score-based tertiary triage policies outperform non-score-based tertiary triage policies including compliance with the German Triage Act. Based on our simulation model, a SAPS II score-based tertiary triage policy reduces mortality in the ICU by up to 18 percentage points. The longer the queue of critical care patients waiting for ICU treatment and the larger the maximum number of patients subject to tertiary triage, the greater the effect on the reduction of mortality in the ICU., Conclusion: A SAPS II score-based tertiary triage policy was superior in our simulation model. Random allocation or "first come, first served" policies yield the lowest survival rates, as will adherence to the new German Triage Act. An interdisciplinary discussion including an ethical and legal perspective is important for the social interpretation of our data-driven results., (© 2024. The Author(s).)

Globally, cardiovascular diseases (CVD) are one of the significant causes of death and are considered a major concern of human society. One of the most crucial objectives of scientists is to reveal the mechanisms associated with the pathogenesis of CVD, which has attracted the attention of many scientists. Accumulating evidence showed that the signal transducer and activator of transcription (STAT) signaling pathway is involved in various physiological and pathological processes. According to research on the molecular mechanisms of CVDs, the STAT family of proteins is one of the most crucial players in these diseases. Numerous studies have demonstrated the undeniable relevance of STAT family proteins in various CVDs. The aim of this review is to shed light on how STAT signaling pathways are related to CVD and the potential for using these signaling pathways as therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The integration of palliative medicine is an important component in the treatment of various advanced diseases. While a German S3 guideline on palliative medicine exists for patients with incurable cancer, a recommendation for non-oncological patients and especially for palliative patients presenting in the emergency department or intensive care unit is missing to date. Based on the present consensus paper, the palliative care aspects of the respective medical disciplines are addressed. The timely integration of palliative care aims to improve quality of life and symptom control in clinical acute and emergency medicine as well as intensive care., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes. Methods: Male C57BL/6J mice were fed a high fat diet for 26 weeks. Twelve weeks into the high fat diet feeding period, mice received an intraperitoneal injection of streptozotocin before being followed for the remaining 14 weeks (DMHFD mice). After 26 weeks, mice were fed a high fat diet containing finerenone (100 mg/kg diet) or high fat diet alone for a further 2 weeks. Cell culture experiments were performed in primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, and MDCK cells. Results: DMHFD mice developed albuminuria, glomerular mesangial expansion, and diastolic dysfunction (decreased E/A ratio). Glp1r and Gcgr were predominantly expressed in arteriolar VSMCs and distal nephron structures of mouse kidneys respectively, whereas Gipr was the predominant of the three transcripts in mouse hearts. Kidney Glp1r and Gcgr and cardiac Gipr mRNA levels were reduced in DMHFD mice and this reduction was negated or attenuated with finerenone. Mechanistically, finerenone attenuated upregulation of the profibrotic growth factor Ccn2 in DMHFD kidneys, whereas recombinant CCN2 downregulated Glp1r and Gcgr in VSMCs and MDCK cells respectively. Conclusions: Through its anti-fibrotic actions, finerenone reverses Glp1r and Gcgr downregulation in the diabetic kidney. Both finerenone and GLP-1R agonists have proven cardiorenal benefits, whereas receptor co-agonists are approved or under development. The current findings provide preclinical rationale for the combined use of finerenone with the GLP-1R agonist family. They also provide mechanism of action insights into the potential benefit of finerenone in people with diabetes for whom GLP-1R agonists or co-agonists may not be indicated. [ABSTRACT FROM AUTHOR]

IL-6 remains a key molecule of the cytokine storms characterizing COVID-19, exerting both proinflammatory and anti-inflammatory effects. Emerging research underscores the significance of IL-6 trans-signaling over classical signaling pathways, which has shifted the focus of therapeutic strategies. Additionally, the synergistic action of TNF-α and IFN-γ has been found to induce inflammatory cell death through PANoptosis, further amplifying the severity of cytokine storms. Long COVID-19 patients, as well as those with cytokine storms triggered by other conditions, exhibit distinct laboratory profiles, indicating the need for targeted approaches to diagnosis and management. Growing evidence also highlights the gut microbiota's crucial role in modulating the immune response during COVID-19 by affecting cytokine production, adding further complexity to the disease's immunological landscape. Targeted intervention strategies should focus on specific cytokine cutoffs, though accurate cytokine quantification remains a clinical challenge. Current treatment strategies are increasingly focused on inhibiting IL-6 trans-signaling, which offers promise for more precise therapeutic approaches to manage hyperinflammatory responses in COVID-19. In light of recent discoveries, this review summarizes key research findings on cytokine storms, particularly their role in COVID-19 and other inflammatory conditions. It explores emerging therapeutic strategies targeting cytokines like IL-6, TNF-α, and IFN-γ, while also addressing open questions, such as the need for better biomarkers to detect and manage cytokine storms. Additionally, the review highlights ongoing challenges in developing targeted treatments that mitigate hyperinflammation without compromising immune function, emphasizing the importance of continued research in this field. [ABSTRACT FROM AUTHOR]

Background: The swift advancement of intensive care medicine, coupled with technological possibilities, has prompted numerous ethical inquiries regarding decision-making processes concerning the withholding or withdrawal of treatment due to medical futility. This study seeks to delineate the decision-making approaches employed by intensive care physicians in Türkiye when faced with medical futility at the end of life, along with an ethical evaluation of these practices. Methods: Grounded theory, a qualitative analysis method was employed, conducting semi-structured, in-depth interviews with eleven intensive care physicians in Türkiye. The subsequent text analysis was carried out using MAXQDA software. Results: Participants assert that the decisions made by Turkish physicians determine whether treatment is futile, rely on medical consensus, and lack a standardized decision-making process. The decisions are influenced by legal and social pressures, resource constraints, and occasional conflicts of interest. The significance of professional hierarchy is notable, with limited consideration given to the opinions of nurses and other staff. The unstructured medical consensus processes are shaped by normative concepts such as benefit, age, justice, and conscience. Furthermore, it was observed that the conscientious opinions of physicians carry more weight than adherence to ethical principles and guidelines. Conclusion: To create optimal conditions for doctors to make ethically justifiable decisions, the dynamics within the treatment team should be improved, emphasizing the minimization of hierarchy, and ensuring the active participation of all team members in the decision-making process. Additionally, efforts should be directed toward narrowing the gap between the conscience of the individual doctor and established ethical principles. A potential solution lies in the nationwide implementation of clinical ethics committees and the establishing of clinical ethics guidelines, aiming to address, and overcome the identified challenges. [ABSTRACT FROM AUTHOR]

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Lower limb arterial occlusive disease is treated with intraluminal devices, such as paclitaxel (PTX)-coated balloons (PCBs); however, post-procedural restenosis remains a significant challenge. NLRP3 activation is known to play a significant role in atherosclerosis, but its involvement in restenosis following PCB intervention remains to be investigated. We identified that NLRP3 was differentially expressed in lower-limb arterial tissues sourced from healthy controls and patients with arterial occlusive disease. Through cell experiments, we confirmed that PTX is involved in the activation of NLRP3. Subsequently, we demonstrated that NLRP3 activation promotes the proliferation and migration of vascular smooth muscle cell (VSMC), thereby reducing their sensitivity to PTX. NLRP3 activation also stimulates the secretion of the inflammatory cytokine interleukin IL-1β. RNA sequencing of IL-1β-treated VSMC revealed the upregulation of BRD4 and LIN9. Further mechanistic investigations confirmed that IL-1β facilitates BRD4 recruitment, leading to enhanced LIN9 expression. The transcription factor LIN9 binds to the promoter region of the cell-cycle regulator AURKA, thereby promoting its transcription and subsequently upregulating the expression of the cell proliferation-associated molecule FOXM1. These processes ultimately mediate the proliferation, migration, and PTX resistance of VSMC. Additionally, we discovered that JQ1 inhibited the overexpression of the above molecules, and exhibited a synergistic effect with PTX. Our conclusions were validated through in vivo experiments in Sprague-Dawley rats. Collectively, our findings provide insights into the molecular mechanisms underlying restenosis following PCB therapy, and suggest that the combined use of JQ1 and PTX devices may represent a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

Endothelial shear stress is a tangential stress derived from the friction of the flowing blood on the endothelial surface of the arterial wall and is expressed in units of force/unit area (dyne/cm2). Branches and bends of arteries are exposed to complex blood flow patterns that generate low or oscillatory endothelial shear stress, which impairs glycocalyx integrity, cytoskeleton arrangement and endothelial junctions (adherens junctions, tight junctions, gap junctions), thus increasing endothelial permeability. The lipoproteins and inflammatory cells penetrating intima due to the increased endothelial permeability characterizes the pathological changes in early stage of atherosclerosis. Endothelial cells are critical sensors of shear stress, however, the mechanisms by which the complex shear stress regulate endothelial permeability in atherosclerosis remain unclear. In this review, we focus on the molecular mechanisms of the endothelial permeability induced by low or oscillatory shear stress, which will shed a novel sight in early stage of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: The spread of several severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants of concern (VOCs) has repeatedly led to increasing numbers of coronavirus disease 2019 (COVID-19) patients in German intensive care units (ICUs), resulting in capacity shortages and even transfers of COVID-19 intensive care patients between federal states in late 2021. In this respect, there is scarce evidence on the impact of predominant VOCs in German ICUs at the population level. Methods: A retrospective cohort study was conducted from July 01, 2021, to May 31, 2022, using daily nationwide inpatient billing data from German hospitals on COVID-19 intensive care patients and SARS-CoV-2 sequence data from Germany. A multivariable Poisson regression analysis was performed to estimate the incidence rate ratios (IRRs) of transfer (to another hospital during inpatient care), discharge (alive) and death of COVID-19 intensive care patients associated with Delta or Omicron, adjusted for age group and sex. In addition, a multistate approach was used for the clinical trajectories of COVID-19 intensive care patients to estimate their competing risk of transfer, discharge or death associated with Delta or Omicron, specifically concerning patient age. Results: A total of 6046 transfers, 33256 discharges, and 12114 deaths were included. Poisson regression analysis comparing Omicron versus Delta yielded an estimated adjusted IRR of 1.23 (95% CI 1.16–1.30) for transfers, 2.27 (95% CI 2.20–2.34) for discharges and 0.98 (95% CI 0.94–1.02) for deaths. For ICU deaths in particular, the estimated adjusted IRR increased from 0.14 (95% CI 0.08–0.22) for the 0–9 age group to 4.09 (95% CI 3.74–4.47) for those aged 90 and older compared to the reference group of 60-69-year-olds. Multistate analysis revealed that Omicron was associated with a higher estimated risk of discharge for COVID-19 intensive care patients across all ages, while Delta infection was associated with a higher estimated risk of transfer and death. Conclusions: Retrospective, nationwide comparisons of transfers, discharges and deaths of COVID-19 intensive care patients during Delta- and Omicron-dominated periods in Germany suggested overall less severe clinical trajectories associated with Omicron. Age was confirmed to be an important determinant of fatal clinical outcomes in COVID-19 intensive care patients, necessitating close therapeutic care for elderly people and appropriate public health control measures. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a kind of myocardial disease that occurs in diabetes patients and cannot be explained by hypertensive heart disease, coronary atherosclerotic heart disease and other heart diseases. Its pathogenesis may be closely related to programmed cell death, oxidative stress, intestinal microbes and micro-RNAs. The excessive activation of mineralocorticoid receptors (MR) in DCM can cause damage to the heart and kidneys. The third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone, can effectively block MR, thus playing a role in protecting the heart and kidneys. This review mainly introduces the classification of MRA, and the mechanism of action, applications and limitations of finerenone in DCM, in order to provide reference for the study of treatment plans for DCM patients. [ABSTRACT FROM AUTHOR]

Objectives: Heart failure (HF) is a global health concern with rising incidence and poor prognosis. While the essential role of nutritional and dietary strategies in HF patients is acknowledged in the existing scientific guidelines and clinical practice, there are no comprehensive nutritional recommendations for optimal dietary management of HF. Methods: In this review, we discuss results from recent studies on the obesity paradox and the effects of calorie restriction and weight loss, intermittent fasting, the Western diet, the Mediterranean diet, the ketogenic diet, and the DASH diet on HF progression. Results: Many of these strategies remain under clinical and basic investigation for their safety and efficacy, and there is considerable heterogeneity in the observed response, presumably because of heterogeneity in the pathogenesis of different types of HF. In addition, while specific aspects of cardiac metabolism, such as changes in ketone body utilization, might underlie the effects of certain dietary strategies on the heart, there is a critical divide between supplement strategies (i.e., with ketones) and dietary strategies that impact ketogenesis. Conclusion: This review aims to highlight this gap by exploring emerging evidence supporting the importance of personalized dietary strategies in preventing progression and improving outcomes in the context of HF. [ABSTRACT FROM AUTHOR]

Introduction: The proportion of very elderly patients in the intensive care unit (ICU) is expected to rise. Furthermore, patients are likely more prone to suffer a cardiac arrest (CA) event within the ICU. The occurrence of intensive care unit cardiac arrest (ICU-CA) is associated with high mortality. To date, the incidence of ICU-CA and its clinical impact on outcome in the very old (≥ 90 years) patients treated is unknown. Methods: Retrospective analysis of all consecutive critically ill patients ≥ 90 years admitted to the ICU of a tertiary care university hospital in Hamburg (Germany). All patients suffering ICU-CA were included and CA characteristics and functional outcome was assessed. Clinical course and outcome were assessed and compared between the subgroups of patients with and without ICU-CA. Results: 1,108 critically ill patients aged ≥ 90 years were admitted during the study period. The median age was 92.3 (91.0–94.2) years and 67% (n = 747) were female. 2% (n = 25) of this cohort suffered ICU-CA after a median duration 0.5 (0.2–3.2) days of ICU admission. The presumed cause of ICU-CA was cardiac in 64% (n = 16). The median resuscitation time was 10 (2–15) minutes and the initial rhythm was shockable in 20% (n = 5). Return of spontaneous circulation (ROSC) could be achieved in 68% (n = 17). The cause of ICU admission was primarily medical in the total cohort (ICU-CA: 48% vs. No ICU-CA: 34%, p = 0.13), surgical - planned (ICU-CA: 32% vs. No ICU-CA: 37%, p = 0.61) and surgical - unplanned/emergency (ICU-CA: 43% vs. No ICU-CA: 28%, p = 0.34). The median Charlson Comorbidity Index (CCI) was 2 (1–3) points for patients with ICU-CA and 1 (0–2) for patients without ICU-CA (p = 0.54). Patients with ICU-CA had a higher disease severity according to SAPS II (ICU-CA: 54 vs. No ICU-CA: 36 points, p < 0.001). Patients with ICU-CA had a higher rate of mechanically ventilation (ICU-CA: 64% vs. No ICU-CA: 34%, p < 0.01) and required vasopressor therapy more often (ICU-CA: 88% vs. No ICU-CA: 41%, p < 0.001). The ICU and in-hospital mortality was 88% (n = 22) and 100% (n = 25) in patients with ICU-CA compared to 17% (n = 179) and 28% (n = 306) in patients without ICU-CA. The mortality rate for patients with ICU-CA was observed to be 88% (n = 22) in the ICU and 100% (n = 25) in-hospital. In contrast, patients without ICU-CA had an in-ICU mortality rate of 17% (n = 179) and an in-hospital mortality rate of 28% (n = 306) (both p < 0.001). Conclusion: The occurrence of ICU-CA in very elderly patients is rare but associated with high mortality. Providing CPR in this cohort did not lead to long-term survival at our centre. Very elderly patients admitted to the ICU likely benefit from supportive care only and should probably not be resuscitated due to poor chance of survival and ethical considerations. Providing personalized assurances that care will remain appropriate and in accordance with the patient's and family's wishes can optimise compassionate care while avoiding futile life-sustaining interventions. [ABSTRACT FROM AUTHOR]

The purinergic signaling system is an evolutionarily conserved and critical regulatory circuit that maintains homeostatic balance across various organ systems and cell types by providing compensatory responses to diverse pathologies. Despite cardiovascular diseases taking a leading position in human morbidity and mortality worldwide, pulmonary diseases represent significant health concerns as well. The endothelium of both pulmonary and systemic circulation (bronchial vessels) plays a pivotal role in maintaining lung tissue homeostasis by providing an active barrier and modulating adhesion and infiltration of inflammatory cells. However, investigations into purinergic regulation of lung endothelium have remained limited, despite widespread recognition of the role of extracellular nucleotides and adenosine in hypoxic, inflammatory, and immune responses within the pulmonary microenvironment. In this review, we provide an overview of the basic aspects of purinergic signaling in vascular endothelium and highlight recent studies focusing on pulmonary microvascular endothelial cells and endothelial cells from the pulmonary artery vasa vasorum. Through this compilation of research findings, we aim to shed light on the emerging insights into the purinergic modulation of pulmonary endothelial function and its implications for lung health and disease. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cytokine storm in severe COVID-19 is responsible for irreversible tissue damage and death. Soluble mediators from the TNF superfamily, their correlation with clinical outcome, and the use of TNF receptors as a potent predictor for clinical outcome were evaluated. Methods: Severe COVID-19 patients had the levels of soluble mediators from the TNF superfamily quantified and categorized according to the clinical outcome (death versus survival). Statistical modeling was performed to predict clinical outcomes. Results: COVID-19 patients have elevated serum levels from the TNF superfamily. Regardless of sex and age, the sTNFRI levels were observed to be significantly higher in deceased patients from the first weeks following the onset of symptoms. We analyzed hematological parameters and inflammatory markers, and there was a difference between the groups for the following factors: erythrocytes, hemoglobin, hematocrit, leukocytes, neutrophils, band cells, lymphocytes, monocytes, CRP, IL-8, IFN-γ, IL-10, IL-6, IL-4, IL-2, leptin MIF sCD40L, and sTNFRI (p < 0.05). A post hoc analysis showed an inferential capacity over 70% for some hematological markers, CRP, and inflammatory mediators in deceased patients. sTNFRI was strongly associated with death, and the sTNFRI/sTNFRII ratio differed between outcomes (p < 0.001; power above 90%), highlighting the impact of these proteins on clinical results. The final logistic model, including sTNFRI/sTNFRII and CRP, indicated high sensitivity, specificity, accuracy, and an eight-fold higher odds ratio for an unfavorable outcome. Conclusions: The joint use of the sTNFRI/sTNFRII ratio with CRP proves to be a promising tool to assist in the clinical management of patients hospitalized for COVID-19. [ABSTRACT FROM AUTHOR]

The recent global COVID-19 pandemic has had a profound and enduring impact, resulting in substantial loss of life. The scientific community has responded unprecedentedly by investigating various aspects of the crisis, particularly focusing on the acute phase of COVID-19. The roles of the viral load, cytokines, and chemokines during the acute phase and in the context of patients who experienced enduring symptoms upon infection, so called Post-Acute Sequelae of COVID-19 or PASC, have been studied extensively. Here, in this review, we offer a virologist's perspective on PASC, highlighting the dynamics of SARS-CoV-2 viral loads, cytokines, and chemokines in different organs of patients across the full clinical spectrum of acute-phase disease. We underline that the probability of severe or critical disease progression correlates with increased viral load levels detected in the upper respiratory tract (URT), lower respiratory tract (LRT), and plasma. Acute-phase viremia is a clear, although not unambiguous, predictor of PASC development. Moreover, both the quantity and diversity of functions of cytokines and chemokines increase with acute-phase disease severity. Specific cytokines remain or become elevated in the PASC phase, although the driving factor of ongoing inflammation found in patients with PASC remains to be investigated. The key findings highlighted in this review contribute to a further understanding of PASC and their differences and overlap with acute disease. [ABSTRACT FROM AUTHOR]