The design of the PRINCESS 2 trial: A randomized trial to study the impact of ultrafast hypothermia on complete neurologic recovery after out-of-hospital cardiac arrest with initial shockable rhythm.

BACKGROUND: Delayed hypothermia, initiated after hospital arrival, several hours after cardiac arrest with 8-10 hours to reach the target temperature, is likely to have limited impact on overall survival. However, the effect of ultrafast hypothermia, i.e., delivered intra-arrest or immediately after return of spontaneous circulation (ROSC), on functional neurologic outcome after out-of-hospital cardiac arrest (OHCA) is unclear. In two prior trials, prehospital trans-nasal evaporative intra-arrest cooling was safe, feasible and reduced time to target temperature compared to delayed cooling. Both studies showed trends towards improved neurologic recovery in patients with shockable rhythms. The aim of the PRINCESS2-study is to assess whether cooling, initiated either intra-arrest or immediately after ROSC, followed by in-hospital hypothermia, significantly increases survival with complete neurologic recovery as compared to standard normothermia care, in OHCA patients with shockable rhythms. METHODS/DESIGN: In this investigator-initiated, randomized, controlled trial, the emergency medical services (EMS) will randomize patients at the scene of cardiac arrest to either trans-nasal cooling within 20 minutes from EMS arrival with subsequent hypothermia at 33°C for 24 hours after hospital admission (intervention), or to standard of care with no prehospital or in-hospital cooling (control). Fever (>37,7°C) will be avoided for the first 72 hours in both groups. All patients will receive post resuscitation care and withdrawal of life support procedures according to current guidelines. Primary outcome is survival with complete neurologic recovery at 90 days, defined as modified Rankin scale (mRS) 0-1. Key secondary outcomes include survival to hospital discharge, survival at 90 days and mRS 0-3 at 90 days. In total, 1022 patients are required to detect an absolute difference of 9% (from 45 to 54%) in survival with neurologic recovery (80% power and one-sided α=0,025, ß=0,2) and assuming 2,5% lost to follow-up. Recruitment starts in Q1 2024 and we expect maximum enrolment to be achieved during Q4 2024 at 20-25 European and US sites. DISCUSSION: This trial will assess the impact of ultrafast hypothermia applied on the scene of cardiac arrest, as compared to normothermia, on 90-day survival with complete neurologic recovery in OHCA patients with initial shockable rhythm. TRIAL REGISTRATION: NCT06025123.

Prehospital emergency medicine research by additional teams on scene - Concepts and lessons learned.

While the initial minutes of acute emergencies significantly influence clinical outcomes, prehospital research often receives inadequate attention due to several challenges. Retrospective chart reviews carry the risk of incomplete and inaccurate data. Furthermore, prehospital intervention trials frequently encounter difficulties related to extensive training requirements, even during the planning phase. Consequently, we have implemented prospective research concepts involving additional paramedics and physicians directly at the scene during major emergency calls. Three concepts were used: (I) Paramedic field supervisor units, (II) a paramedic + physician field supervisor unit, (III) a special physician-based research car. This paper provides insights into our historical perspective, the current situation, and the lessons learned while overcoming certain barriers and using existing and novel facilitators. Our objective is to support other research groups with our experiences in their planning of upcoming prehospital trials.

A ventricular fibrillation cardiac arrest model with extracorporeal cardiopulmonary resuscitation in rats: 8 minutes arrest time leads to increased myocardial damage but does not increase neuronal damage compared to 6 minutes.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) is an emerging strategy in highly selected patients with refractory cardiac arrest (CA). Animal models can help to identify new therapeutic strategies to improve neurological outcome and cardiac function after global ischemia in CA. Aim of the study was to establish a reproducible ECPR rat model of ventricular fibrillation CA (VFCA) that leads to consistent neuronal damage with acceptable long-term survival rates, which can be used for future research. Materials and methods: Male Sprague Dawley rats were resuscitated with ECPR from 6 min (n = 15) and 8 min (n = 16) VFCA. Animals surviving for 14 days after return of spontaneous resuscitation (ROSC) were compared with sham operated animals (n = 10); neurological outcome was assessed daily until day 14. In the hippocampal cornu ammonis 1 region viable neurons were counted. Microglia and astrocyte reaction was assessed by Iba1 and GFAP immunohistochemistry, and collagen fibers in the myocardium were detected in Azan staining. QuPath was applied for quantification. Results: Of the 15 rats included in the 6 min CA group, all achieved ROSC (100%) and 10 (67%) survived to 14 days; in the 8 min CA group, 15 (94%) achieved ROSC and 5 (31%) reached the endpoint. All sham animals (n = 10) survived 2 weeks. The quantity of viable neurons was significantly decreased, while the area displaying Iba1 and GFAP positive pixels was significantly increased in the hippocampus across both groups that experienced CA. Interestingly, there was no difference between the two CA groups regarding these changes. The myocardium in the 8 min CA group exhibited significantly more collagen fibers compared to the sham animals, without differences between 6- and 8-min CA groups. However, this significant increase was not observed in the 6 min CA group. Conclusion: Our findings indicate a uniform occurrence of neuronal damage in the hippocampus across both CA groups. However, there was a decrease in survival following an 8-min CA. Consequently, a 6-min duration of CA resulted in predictable neurological damage without significant cardiac damage and ensured adequate survival rates up to 14 days. This appears to offer a reliable model for investigating neuroprotective therapies.

Sequencing of SARS-CoV-2 RNA Fragments in Wastewater Detects the Spread of New Variants during Major Events.

The sequencing of SARS-CoV-2 RNA in wastewater is an unbiased method to detect the spread of emerging variants and to track regional infection dynamics, which is especially useful in case of limited testing and clinical sequencing. To test how major international events influence the spread of new variants we have sequenced SARS-CoV-2 RNA in the wastewater samples of Davos, Landquart, Lostallo, and St. Moritz in the Swiss canton of Grisons in the time around the international sports competitions in Davos and St. Moritz in December 2021, and additionally in May 2022 and January 2023 in Davos and St. Moritz during the World Economic Forum (WEF) in Davos. The prevalence of the variants identified from the wastewater sequencing data showed that the Omicron variant BA.1 had spread in Davos and St. Moritz during the international sporting events hosted there in December 2021. This spread was associated with an increase in case numbers, while it was not observed in Landquart and Lostallo. Another instance of new variant spread occurred during the WEF in January 2023, when the Omicron variant BA.2.75 arrived in Davos but not in St. Moritz. We can therefore conclude that major international events promote the spread of new variants in the respective host region, which has important implications for the protective measures that should be taken.

HDL-Related Parameters and COVID-19 Mortality: The Importance of HDL Function.

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality.

Differences in Automated External Defibrillator Types in Out-of-Hospital Cardiac Arrest Treated by Police First Responders.

Background: Police first responder systems also including automated external defibrillation (AED) has in the past shown considerable impact on favourable outcomes after out-of-hospital cardiac arrest (OHCA). While short hands-off times in chest compressions are known to be beneficial, various AED models use different algorithms, inducing longer or shorter durations of crucial timeframes along basic life support (BLS). Yet, data on details of these differences, and also of their potential impact on clinical outcomes are scarce. Methods: For this retrospective observational study, patients with OHCA of presumed cardiac origin and initially shockable rhythm treated by police first responders in Vienna, Austria, between 01/2013 and 12/2021 were included. Data from the Viennese Cardiac Arrest Registry and AED files were extracted, and exact timeframes were analyzed. Results: There were no significant differences in the 350 eligible cases in demographics, return of spontaneous circulation, 30-day survival, or favourable neurological outcome between the used AED types. However, the Philips HS1 and -FrX AEDs showed immediate rhythm analysis after electrode placement (0 [0-1] s) and almost no shock loading time (0 [0-1] s), as opposed to the LP CR Plus (3 [0-4] and 6 [6-6] s, respectively) and LP 1000 (3 [2-10] and 6 [5-7] s, respectively). On the other hand, the HS1 and -FrX had longer analysis times of 12 [12-16] and 12 [11-18] s than the LP CR Plus (5 [5-6] s) and LP 1000 (6 [5-8] s). The duration from when the AED was turned on until the first defibrillation were 45 [28-61] s (Philips FrX), 59 [28-81] s (LP 1000), 59 [50-97] s (HS1), and 69 [55-85] s (LP CR Plus). Conclusion: In a retrospective analysis of OHCA-cases treated by police first responders, we could not find significant differences in clinical patient outcomes concerning the respective used AED model. However, various differences in time durations (e.g., electrode placement to rhythm analysis, analysis duration, or AED turned on until first defibrillation) along the BLS algorithm were seen. This opens up the question of AED-adaptations and tailored training methods for professional first responders.

Association Between Postresuscitation 12-Lead ECG Features and Early Mortality After Out-of-Hospital Cardiac Arrest: A Post Hoc Subanalysis of the PEACE Study.

Background Once the return of spontaneous circulation after out-of-hospital cardiac arrest is achieved, a 12-lead ECG is strongly recommended to identify candidates for urgent coronary angiography. ECG has no apparent role in mortality risk stratification. We aimed to assess whether ECG features could be associated with 30-day survival in patients with out-of-hospital cardiac arrest. Methods and Results All the post-return of spontaneous circulation ECGs from January 2015 to December 2018 in 3 European centers (Pavia, Lugano, and Vienna) were collected. Prehospital data were collected according to the Utstein style. A total of 370 ECGs were collected: 287 men (77.6%) with a median age of 62 years (interquartile range, 53-70 years). After correction for the return of spontaneous circulation-to-ECG time, age >62 years (hazard ratio [HR], 1.78 [95% CI, 1.21-2.61]; P=0.003), female sex (HR, 1.5 [95% CI, 1.05-2.13]; P=0.025), QRS wider than 120 ms (HR, 1.64 [95% CI, 1.43-1.87]; P<0.001), the presence of a Brugada pattern (HR, 1.49 [95% CI, 1.39-1.59]; P<0.001), and the presence of ST-segment elevation in >1 segment (HR, 1.75 [95% CI, 1.59-1.93]; P<0.001) were independently associated with 30-day mortality. A score ranging from 0 to 26 was created, and by dividing the population into 3 tertiles, 3 classes of risk were found with significantly different survival rate at 30 days (score 0-4, 73%; score 5-7, 66%; score 8-26, 45%). Conclusions The post-return of spontaneous circulation ECG can identify patients who are at high risk of mortality after out-of-hospital cardiac arrest earlier than other forms of prognostication. This provides important risk stratification possibilities in postcardiac arrest care that could help to direct treatments and improve outcomes in patients with out-of-hospital cardiac arrest.

Hypothermia for neuroprotection in adults after cardiac arrest.

BACKGROUND: Good neurological outcome after cardiac arrest is difficult to achieve. Interventions during the resuscitation phase and treatment within the first hours after the event are critical for a favourable prognosis. Experimental evidence suggests that therapeutic hypothermia is beneficial, and several clinical studies on this topic have been published. This review was originally published in 2009; updated versions were published in 2012 and 2016. OBJECTIVES: To evaluate the benefits and harms of therapeutic hypothermia after cardiac arrest in adults compared to standard treatment. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 30 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults comparing therapeutic hypothermia after cardiac arrest with standard treatment (control). We included studies with adults cooled by any method, applied within six hours of cardiac arrest, to target body temperatures of 32 °C to 34 °C. Good neurological outcome was defined as no or only minor brain damage allowing people to live an independent life. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. neurological recovery. Our secondary outcomes were 2. survival to hospital discharge, 3. quality of life, 4. cost-effectiveness and 5. ADVERSE EVENTS: We used GRADE to assess certainty. MAIN RESULTS: We found 12 studies with 3956 participants reporting the effects of therapeutic hypothermia on neurological outcome or survival. There were some concerns about the quality of all the studies, and two studies had high risk of bias overall. When we compared conventional cooling methods versus any type of standard treatment (including a body temperature of 36 °C), we found that participants in the therapeutic hypothermia group were more likely to reach a favourable neurological outcome (risk ratio (RR) 1.41, 95% confidence interval (CI) 1.12 to 1.76; 11 studies, 3914 participants). The certainty of the evidence was low. When we compared therapeutic hypothermia with fever prevention or no cooling, we found that participants in the therapeutic hypothermia group were more likely to reach a favourable neurological outcome (RR 1.60, 95% CI 1.15 to 2.23; 8 studies, 2870 participants). The certainty of the evidence was low. When we compared therapeutic hypothermia methods with temperature management at 36 °C, there was no evidence of a difference between groups (RR 1.78, 95% CI 0.70 to 4.53; 3 studies; 1044 participants). The certainty of the evidence was low. Across all studies, the incidence of pneumonia, hypokalaemia and severe arrhythmia was increased amongst participants receiving therapeutic hypothermia (pneumonia: RR 1.09, 95% CI 1.00 to 1.18; 4 trials, 3634 participants; hypokalaemia: RR 1.38, 95% CI 1.03 to 1.84; 2 trials, 975 participants; severe arrhythmia: RR 1.40, 95% CI 1.19 to 1.64; 3 trials, 2163 participants). The certainty of the evidence was low (pneumonia, severe arrhythmia) to very low (hypokalaemia). There were no differences in other reported adverse events between groups. AUTHORS' CONCLUSIONS: Current evidence suggests that conventional cooling methods to induce therapeutic hypothermia may improve neurological outcomes after cardiac arrest. We obtained available evidence from studies in which the target temperature was 32 °C to 34 °C.

Obesity Affects Maternal and Neonatal HDL Metabolism and Function.

Pregravid obesity is one of the major risk factors for pregnancy complications such as gestational diabetes mellitus (GDM) and an increased risk of cardiovascular events in children of affected mothers. However, the biological mechanisms that underpin these adverse outcomes are not well understood. High-density lipoproteins (HDLs) are antiatherogenic by promoting the efflux of cholesterol from macrophages and by suppression of inflammation. Functional impairment of HDLs in obese and GDM-complicated pregnancies may have long-term effects on maternal and offspring health. In the present study, we assessed metrics of HDL function in sera of pregnant women with overweight/obesity of the DALI lifestyle trial (prepregnancy BMI ≥ 29 kg/m2) and women with normal weight (prepregnancy BMI < 25 kg/m2), as well as HDL functionalities in cord blood at delivery. We observed that pregravid obesity was associated with impaired serum antioxidative capacity and lecithin−cholesterol acyltransferase activity in both mothers and offspring, whereas maternal HDL cholesterol efflux capacity was increased. Interestingly, functionalities of maternal and fetal HDL correlated robustly. GDM did not significantly further alter the parameters of HDL function and metabolism in women with obesity, so obesity itself appears to have a major impact on HDL functionality in mothers and their offspring.

[More free time for me? Effects of a group intervention for informal caregivers based on routine data from the SVLFG long-term care insurance]. / Mehr Freiraum für mich? Effekte einer Gruppenintervention für pflegende Angehörige anhand von Routinedaten der SVLFG-Pflegekasse.

BACKGROUND: The intervention is a multiday health program of the Social Insurance for Agriculture, Forestry and Horticulture (SVLFG) for informal caregivers. AIM OF THE WORK: Does the intervention increase the use of outside help to gain free time for self-care? MATERIAL AND METHODS: Using a quasi-experimental within-design, we analyze annual benefit data from the SVLFG long-term care insurance for the cluster sample Bavaria from 2017 to 2020 with intervention in 2018/2019. Using fixed effects panel regressions, we determine the effect heterogeneity for care relationship, duration of care and degree of care, adjusting for period effects (intervention and comparison group: 88 and 6045 persons with 207 and 16,091 observations, respectively). RESULT: After the intervention, the use of services for outside help tends to be higher than before. The effect is significantly more pronounced with increasing care level, care within the partnership and shorter care duration. With care within the partnership, start of care before 1 year and care level 4/5, more outside help is used afterwards for 1160 € (p < 0.001) than before. DISCUSSION: Design and statistical method would allow a causal conclusion; however, in view of the limitations, in particular the small number of cases in the intervention group and the only limited characteristics available to control for time-dynamic heterogeneity, caution is advisable.

A Commentary on the Effect of Targeted Temperature Management in Patients Resuscitated from Cardiac Arrest.

The members of the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force have written a comprehensive summary of trials of the effectiveness of induced hypothermia (IH) or targeted temperature management (TTM) in comatose patients after cardiac arrest (CA). However, in-depth analysis of these studies is incomplete, especially since there was no significant difference in primary outcome between hypothermia versus normothermia in the recently reported TTM2 trial. We critically appraise trials of IH/TTM versus normothermia to characterize reasons for the lack of treatment effect, based on a previously published framework for what to consider when the primary outcome fails. We found a strong biologic rationale and external clinical evidence that IH treatment is beneficial. Recent TTM trials mainly included unselected patients with a high rate of bystander cardiopulmonary resuscitation. The treatment was not applied as intended, which led to a large delay in achievement of target temperature. While receiving intensive care, sedative drugs were likely used that might have led to increased neurologic damage as were antiplatelet drugs that could be associated with increased acute stent thrombosis in hypothermic patients. It is reasonable to still use or evaluate IH treatment in patients who are comatose after CA as there are multiple plausible reasons why IH compared to normothermia did not significantly improve neurologic outcome in the TTM trials.

Occupational physicians dealing with mental health: between employee and company interests: a qualitative study.

BACKGROUND: Occupational health physicians are increasingly confronted with mental health issues at their workplace. Facing them, most of them feel insecure and not sufficiently trained. Employee's mental well-being depends at the same time on individual and significantly on organizational variables. This complicates the physician's position, since they have to serve many interests. The focus of the present study is to investigate what difficulties occupational health physicians face and how organizational culture and management influence their work. METHODS: Interviews were conducted with N = 25 physicians as part of a training for basic mental health care. Interviews were interpreted using qualitative content analysis. RESULTS: Working with mentally ill employees was difficult for the physicians interviewed. Many felt insecure managing and preventing mental health issues. A need for further education was observed. Environmental factors (organizational culture, management) have a strong impact on the work of an occupational health physician and highlight its systemic dimension. Even though many of our participants report a meanwhile more open attitude towards mental disorders at their workplace, on the level of direct contact to the management prevail descriptions of little acceptance and a high priority of economic outcomes. CONCLUSIONS: More education on topics of mental health is needed for occupational health physicians. Future trainings should consider the intertwined nature of their work and enable them in dealing consciously with other actors in the company. For enhancing employee's mental well-being occupational health physicians could be granted a strengthened position in companies or be supported through more exchange with colleagues in other companies.

HDL Isolated by Immunoaffinity, Ultracentrifugation, or Precipitation is Compositionally and Functionally Distinct.

The HDL proteome has been widely recognized as an important mediator of HDL function. While a variety of HDL isolation methods exist, their impact on the HDL proteome and its associated function remain largely unknown. Here, we compared three of the most common methods for HDL isolation, namely immunoaffinity (IA), density gradient ultracentrifugation (UC), and dextran-sulfate precipitation (DS), in terms of their effects on the HDL proteome and associated functionalities. We used state-of-the-art mass spectrometry to identify 171 proteins across all three isolation methods. IA-HDL contained higher levels of paraoxonase 1, apoB, clusterin, vitronectin, and fibronectin, while UC-HDL had higher levels of apoA2, apoC3, and α-1-antytrypsin. DS-HDL was enriched with apoA4 and complement proteins, while the apoA2 content was very low. Importantly, size-exclusion chromatography analysis showed that IA-HDL isolates contained subspecies in the size range above 12 nm, which were entirely absent in UC-HDL and DS-HDL isolates. Analysis of these subspecies indicated that they primarily consisted of apoA1, IGκC, apoC1, and clusterin. Functional analysis revealed that paraoxonase 1 activity was almost completely lost in IA-HDL, despite high paraoxonase content. We observed that the elution conditions, using 3M thiocyanate, during IA resulted in an almost complete loss of paraoxonase 1 activity. Notably, the cholesterol efflux capacity of UC-HDL and DS-HDL was significantly higher compared to IA-HDL. Together, our data clearly demonstrate that the isolation procedure has a substantial impact on the composition, subclass distribution, and functionality of HDL. In summary, our data show that the isolation procedure has a significant impact on the composition, subclass distribution and functionality of HDL. Our data can be helpful in the comparison, replication and analysis of proteomic datasets of HDL.

Conceptual Framework of a Psychotherapeutic Consultation in the Workplace: A Qualitative Study.

(1) Background: A new health care offer called 'psychotherapeutic consultation in the workplace' is an early and effective intervention for employees with common mental disorders. Although cost-effective, it lacks a broader roll-out. This might be attributable to undefined context, mechanisms of change, and a lack of communication; therefore, this study explores how the new model works and where problems occur. (2) Methods: Semi-structured interviews on motivation, expectations and experiences with 20 involved experts. Experts were members of the company health promotion team, service users, and cooperating mental health specialists. Analysis was conducted with ATLAS.ti. (3) Results: The conceptual framework comprises three main topics: (a) structured implementation concept; (b) persons involved, shaping the concept's processes; (c) and meaning and function of the offer within the given context. Concerning (c) we found three potential areas of conflict: (1) intra-corporate conflicts, (2) conflicts between company and employee, (3) and conflicts between the company health promotion and the health care system. Category (c) comprises the offer's core characteristics which were described as low-threshold and preventive. Furthermore, the offer was perceived as convenient in handling, confidential, and having immediate impact on a person's well-being. (4) Conclusions: Here we define structures, address the needs of the involved persons, and communicate foreseeable areas of conflict influences whether the implementation of the intervention succeeds.

A moodle course to substitute resuscitation teaching in a medical curriculum during the COVID-19 pandemic: A prospective pilot study.

Background: Face-to-face medical education was restricted during the COVID-19 pandemic, leading to alternative teaching methods. Moodle® (Modular Object-Oriented Dynamic Learning Environment) - an online course format - has not yet been sufficiently evaluated for its feasibility and effectiveness in teaching cardiopulmonary resuscitation. Methods: Medical students in the eighth semester took part in a Moodle® course teaching basic life support, the ABCDE-approach, airway management, and advanced life support. The content was presented using digital background information and interactive videos. A multiple-choice test was conducted at the beginning and at the end of the course. Subjective ratings were included as well. Results: Out of 594 students, who were enrolled in the online course, 531 could be included in this study. The median percentage of correctly answered multiple-choice test questions increased after completing the course [78.9%, interquartile range (IQR) 69.3-86.8 vs. 97.4%, IQR 92.1-100, p < 0.001]. There was no gender difference in the median percentage of correctly answered questions before (female: 79.8%, IQR 70.2-86.8, male: 78.1%, IQR 68.4-86.8, p = 0.412) or after (female: 97.4%, IQR 92.1-100, male: 96.5%, IQR 92.6-100, p = 0.233) the course. On a 5-point Likert scale, 78.7% of students self-reported ≥4 when asked for a subjective increase in knowledge. Noteworthy, on a 10-point Likert scale, male students self-reported their higher confidence in performing CPR [female 6 (5-7), male 7 (6-8), p < 0.001]. Conclusion: The Moodle® course led to a significant increase in theoretical knowledge. It proved to be a feasible substitute for face-to-face courses - both objectively and subjectively.

Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca2+ signalling in heart failure.

Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) versus perinuclear (PN) mitochondria during the development of HF. Here, we use multiple approaches to examine the morphology and functional properties of IF versus PN mitochondria in pressure overload-induced cardiac remodelling in mice, and in non-failing and failing human cardiomyocytes. We demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to depolarization of mitochondrial membrane potential, reactive oxygen species generation and impairment in Ca2+ uptake compared with IF mitochondria at baseline and under physiological stress protocol. We also demonstrate, for the first time to our knowledge, that under normal conditions PN mitochondrial Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and limits nucleoplasmic Ca2+ loading. The loss of PN mitochondrial Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ signalling and alleviation of altered excitation-transcription, which could be an important therapeutic approach to prevent adverse cardiac remodelling. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

The difference between arterial pCO2 and etCO2 after cardiac arrest - Outcome predictor or marker of unfavorable resuscitation circumstances?

INTRODUCTION: In former studies, the arterio-alveolar carbon dioxide gradient (ΔCO2) predicted in-hospital mortality after initially survived cardiac arrest. As early outcome predictors are urgently needed, we evaluated ΔCO2 as predictor for good neurological outcome in our cohort. METHODS: We retrospectively analyzed all patients ≥18 years of age after non-traumatic in- and out of hospital cardiac arrest in the year 2018 from our resuscitation database. Patients without advanced airway management, incomplete datasets or without return of spontaneous circulation were excluded. The first arterial pCO2 after admission and the etCO2 in mmHg at the time of blood sampling were recorded from patient's charts. We then calculated ΔCO2 (pCO2 - etCO2). For baseline analyses, ΔCO2 was dichotomized into a low and high group with separation at the median. Good neurological outcome on day 30, expressed as Cerebral Performance Category 1-2, defined our primary endpoint. Survival to 30 days was used as secondary endpoint. RESULTS: Out of 302 screened patients, 128 remained eligible for analyses. ΔCO2 was lower in 30-day survivors with good neurological outcome (12.2 mmHg vs. 18.8 mmHg, p = 0.009) and in 30-day survivors (12.5 mmHg vs. 20.0 mmHg, p = 0.001). In patients with high ΔCO2, a cardiac etiology of arrest was found less often. They had a higher body mass index, longer duration of resuscitation, higher amounts of epinephrine, lower pO2 levels but both higher pCO2 and blood lactate levels, resulting in lower blood pH and HCO3- levels at admission. In a crude binary logistic regression analysis, ΔCO2 was associated with 30-day neurological outcome (OR = 1.041 per mmHg of ΔCO2, 95% CI 1.008-1.074, p = 0.014). This association persisted after the adjustment for age, sex, witnessed arrest and shockable first rhythm. However, after addition of the duration of resuscitation or the cumulative epinephrine dosage to the model, ΔCO2 lost its association. CONCLUSION: ΔCO2 at admission after a successfully resuscitated cardiac arrest is associated with 30 days survival with good neurological outcome. However, a higher ΔCO2 may rather be a surrogate for unfavorable resuscitation circumstances than an independent outcome predictor.

Adult Respiratory Syncytial Virus Infection and Hypoxic Cardiac Arrest-Coexistent or Causal? A Hypothesis-Generating Case Report.

Respiratory syncytial virus (RSV) is a well-known pathogen in paediatric patients. However, it also causes substantial morbidity and mortality in adults, posing a major healthcare problem. We present a patient with chronic pulmonary conditions and an acute RSV infection, thus leading to cardiac arrest (CA). We speculate that RSV as the causative agent for CA should be considered in post-resuscitation care. From a wider public health perspective, immuno-naivety for RSV caused by the coronavirus disease 2019 pandemic may induce a severe rise in cases, morbidity, and mortality in the future.

ß-Adrenergic Receptor Stimulation Maintains NCX-CaMKII Axis and Prevents Overactivation of IL6R-Signaling in Cardiomyocytes upon Increased Workload.

Excessive ß-adrenergic stimulation and tachycardia are potent triggers of cardiac remodeling; however, their exact cellular effects remain elusive. Here, we sought to determine the potency of ß-adrenergic stimulation and tachycardia to modulate gene expression profiles of cardiomyocytes. Using neonatal rat ventricular cardiomyocytes, we showed that tachycardia caused a significant upregulation of sodium-calcium exchanger (NCX) and the activation of calcium/calmodulin-dependent kinase II (CaMKII) in the nuclear region. Acute isoprenaline treatment ameliorated NCX-upregulation and potentiated CaMKII activity, specifically on the sarcoplasmic reticulum and the nuclear envelope, while preincubation with the ß-blocker propranolol abolished both isoprenaline-mediated effects. On a transcriptional level, screening for hypertrophy-related genes revealed tachycardia-induced upregulation of interleukin-6 receptor (IL6R). While isoprenaline prevented this effect, pharmacological intervention with propranolol or NCX inhibitor ORM-10962 demonstrated that simultaneous CaMKII activation on the subcellular Ca2+ stores and prevention of NCX upregulation are needed for keeping IL6R activation low. Finally, using hypertensive Dahl salt-sensitive rats, we showed that blunted ß-adrenergic signaling is associated with NCX upregulation and enhanced IL6R signaling. We therefore propose a previously unrecognized protective role of ß-adrenergic signaling, which is compromised in cardiac pathologies, in preventing IL6R overactivation under increased workload. A better understanding of these processes may contribute to refinement of therapeutic options for patients receiving ß-blockers.

Out-of-Sample Validity of the PROLOGUE Score to Predict Neurologic Function after Cardiac Arrest.

BACKGROUND: The clinical value of a prognostic score depends on its out-of-sample validity because inaccurate outcome prediction can be not only useless but potentially fatal. We aimed to evaluate the out-of-sample validity of a recently developed and highly accurate Korean prognostic score for predicting neurologic outcome after cardiac arrest in an independent, plausibly related sample of European cardiac arrest survivors. METHODS: Analysis of data from a European cardiac arrest center, certified in compliance with the specifications of the German Council for Resuscitation. The study sample included adults with nontraumatic out-of-hospital cardiac arrest admitted between 2013 and 2018. Exposure was the PROgnostication using LOGistic regression model for Unselected adult cardiac arrest patients in the Early stages (PROLOGUE) score, including 12 clinical variables readily available at hospital admission. The outcome was poor 30-day neurologic function, as assessed using the cerebral performance category scale. The risk of a poor outcome was calculated using the PROLOGUE score regression equation. Predicted risk deciles were compared to observed outcome estimates in a complete-case analysis, a best-case analysis, and a multiple-data-imputation analysis using the Markov chain Monte Carlo method. RESULTS: A total of 1051 patients (median 61 years, IQR 50-71; 29% female) were analyzed. A total of 808 patients (77%) were included in the complete-case analysis. The PROLOGUE score overestimated the risk of poor neurologic outcomes in the range of 40% to 100% predicted risk, involving 63% of patients. The model fit did not improve after missing data imputation. CONCLUSIONS: In a plausibly related sample of European cardiac arrest survivors, risk prediction by the PROLOGUE score was largely too pessimistic and failed to replicate the high accuracy found in the original study. Using the PROLOGUE score as an example, this study highlights the compelling need for independent validation of a proposed prognostic score to prevent potentially fatal mispredictions.