Low LCAT activity is linked to acute decompensated heart failure and mortality in patients with CKD.

Chronic kidney disease (CKD) is often associated with decreased activity of lecithin-cholesterol acyltransferase (LCAT), an enzyme essential for HDL maturation. This reduction in LCAT activity may potentially contribute to an increased risk of cardiovascular mortality in patients with CKD. The objective of this study was to investigate the association between LCAT activity in patients with CKD and the risk of adverse outcomes. We measured serum LCAT activity and characterized lipoprotein profiles using nuclear magnetic resonance spectroscopy in 453 non-dialysis CKD patients from the CARE FOR HOMe study. LCAT activity correlated directly with smaller HDL particle size, a type of HDL potentially linked to greater cardiovascular protection. Over a mean follow-up of 5.0 ± 2.2 years, baseline LCAT activity was inversely associated with risk of death (standardized HR 0.62, 95% CI 0.50-0.76; P < 0.001) and acute decompensated heart failure (ADHF) (standardized HR 0.67, 95% CI 0.52-0.85; P = 0.001). These associations remained significant even after adjusting for other risk factors. Interestingly, LCAT activity was not associated with the incidence of atherosclerotic cardiovascular events or kidney function decline during the follow-up. To conclude, our findings demonstrate that low LCAT activity is independently associated with all-cause mortality and ADHF in patients with CKD, and is directly linked to smaller, potentially more protective HDL subclasses.

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.

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.

[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.

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.

CaMKIIδC Drives Early Adaptive Ca2+ Change and Late Eccentric Cardiac Hypertrophy.

RATIONALE: CaMKII (Ca2+-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca2+ handling and CaMKII activation in hypertrophy and HF. OBJECTIVE: To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice. METHODS AND RESULTS: We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions. CONCLUSIONS: We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKIIδC axis contributes to eccentric hypertrophy and HF.

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.

Endothelial Lipase Modulates Paraoxonase 1 Content and Arylesterase Activity of HDL.

Endothelial lipase (EL) is a strong modulator of the high-density lipoprotein (HDL) structure, composition, and function. Here, we examined the impact of EL on HDL paraoxonase 1 (PON1) content and arylesterase (AE) activity in vitro and in vivo. The incubation of HDL with EL-overexpressing HepG2 cells decreased HDL size, PON1 content, and AE activity. The EL modification of HDL did not diminish the capacity of HDL to associate with PON1 when EL-modified HDL was incubated with PON1-overexpressing cells. The overexpression of EL in mice significantly decreased HDL serum levels but unexpectedly increased HDL PON1 content and HDL AE activity. Enzymatically inactive EL had no effect on the PON1 content of HDL in mice. In healthy subjects, EL serum levels were not significantly correlated with HDL levels. However, HDL PON1 content was positively associated with EL serum levels. The EL-induced changes in the HDL-lipid composition were not linked to the HDL PON1 content. We conclude that primarily, the interaction of enzymatically active EL with HDL, rather than EL-induced alterations in HDL size and composition, causes PON1 displacement from HDL in vitro. In vivo, the EL-mediated reduction of HDL serum levels and the consequently increased PON1-to-HDL ratio in serum increase HDL PON1 content and AE activity in mice. In humans, additional mechanisms appear to underlie the association of EL serum levels and HDL PON1 content.

Extracorporeal cardiopulmonary resuscitation at the emergency department: A retrospective patient selection evaluation.

BACKGROUND: There is an increasing use of extracorporeal life support in refractory cardiac arrest. Recent studies highlighted the importance of an early and accurate patient selection for this invasive procedure. OBJECTIVES: The aim of this study was to retrospectively validate a six-criteria-screening-checklist (witnessed collapse, bystander-cardiopulmonary resuscitation/first medical contact <5 min, shockable, age <70 years, end tidal carbon dioxide >14 mmHg and pupils not anisocoric/distorted/mydriatic) as an early screening tool in patients treated with extracorporeal cardiopulmonary resuscitation (eCPR) at the emergency department. DESIGN: Retrospective observational study. SETTING/PATIENTS: All patients at least 18 years of age with nontraumatic cardiac arrest and without return of spontaneous circulation before eCPR treatment at our department between January 2013 and December 2018 were included in this retrospective observational study. INTERVENTION: No specific intervention was set in this observational study. MAIN OUTCOME MEASURES: Primary outcome was the rate of patients who fulfilled all criteria, secondary outcome was 30-day and 6-month survival in accordance with the criteria. RESULTS: Overall, data from a total of 92 patients were eligible for analyses. Out of these, 27 patients (29%) met all criteria. Patients, who fulfilled all criteria, showed significantly higher odds for 30-day survival [OR 6.0 (95% CI 1.78 to 20.19)] P = 0.004. Patients, who did not fulfil all criteria, showed significantly higher rates of early mortality after eCPR initiation [OR 4.57 (95% CI 1.69 to 12.37)] P = 0.003. CONCLUSION: Patients fulfilling all inclusion criteria showed higher rates of survival after eCPR. Our results affirm that there is a possibility and even an obvious necessity for early patient selection based on standardised criteria before eCPR treatment. Large randomised trials are urgently needed to answer this question accurately.

Metabolic disease and ABHD6 alter the circulating bis(monoacylglycerol)phosphate profile in mice and humans.

Bis(monoacylglycerol)phosphate (BMP) is a phospholipid that is crucial for lipid degradation and sorting in acidic organelles. Genetic and drug-induced lysosomal storage disorders (LSDs) are associated with increased BMP concentrations in tissues and in the circulation. Data on BMP in disorders other than LSDs, however, are scarce, and key enzymes regulating BMP metabolism remain elusive. Here, we demonstrate that common metabolic disorders and the intracellular BMP hydrolase α/ß-hydrolase domain-containing 6 (ABHD6) affect BMP metabolism in mice and humans. In mice, dietary lipid overload strongly affects BMP concentration and FA composition in the liver and plasma, similar to what has been observed in LSDs. Notably, distinct changes in the BMP FA profile enable a clear distinction between lipid overload and drug-induced LSDs. Global deletion of ABHD6 increases circulating BMP concentrations but does not cause LSDs. In humans, nonalcoholic fatty liver disease and liver cirrhosis affect the serum BMP FA composition and concentration. Furthermore, we identified a patient with a loss-of-function mutation in the ABHD6 gene, leading to an altered circulating BMP profile. In conclusion, our results suggest that common metabolic diseases and ABHD6 affect BMP metabolism in mice and humans.

Psychische Erkrankungen im Arbeitskontext ­ eine Verortung im Versorgungssystem.

Work and mental health are closely interrelated. Sick leave rates due to mental illness have constantly been rising for years. Thus, not only companies but also the society as a whole have become more and more aware of the relevance of this topic.At first, various work stress models are outlined in this article. This is followed by an overview of how to classify work-related mental disorders in the ICD and DSM systems. Burnout is explained with regard to terminology, origin and adequate use in clinical practice. Furthermore, the ILO (International Labour Organization) classification of work-related mental disorders is presented. Possible intervention models for the prevention and therapy of work-related mental health problems are discussed. In addition, the most essential components of work-related psychotherapy are pointed out. Finally, corresponding guidelines are put into an international context.

[Waiting Times For Admission Into A Psychotherapeutic Inpatient Treatment - Results of A Prospective Study In South-Württemberg]. / Wartezeiten auf die Aufnahme in eine Psychosomatische Klinik ­ Ergebnisse einer prospektiven Studie in Südwürttemberg.

INTRODUCTION: Waiting times for the admission into a so called psychosomatic hospital in Germany prevent the necessary immediate treatment. They lead to further incapacity for work and chronic manifestation of the disease. It is reported that most psychosomatic hospitals have waiting times, but there are no studies on data on that. Therefore, it was the aim of this study to access prospectively in a defined region, how long it takes for the patients to get an outpatient preliminary talk and thereafter, how long they have to wait for their admission. METHODS: 7 hospitals out of the region of South-Württemberg took part on this study, 2 of them had bigger day hospitals. Data were assessed prospectively in 2015 over 9 months, in total 916 admissions were assessed. RESULTS: The waiting time until a preliminary talk, in which the indication for inpatient treatment was secured, was in the mean 25 days (SD=31). The waiting time after this talk until admission was 56 days (SD=47). Patients who waited for a day treatment had to wait even longer. An urgency remark, given by the therapist of the preliminary talk, as well as a private illness insurance led to shorter waiting times. The diagnosis had no influence on the waiting time. CONCLUSIONS: The waiting times are substantial and imply a burden for the patient and also for the health care system. It is recommended to assess and publish these waiting times on a regularly basis. Politics, but also the actors in the health care system should discuss if and how this deficit can be changed.

[How do users assess the new "Psychosomatic Consultation in the Workplace" model of care? : Results of a controlled observational trial]. / Wie bewerten Nutzer das neue Versorgungsmodell "Die Psychosomatische Sprechstunde im Betrieb"? : Ergebnisse einer kontrollierten Beobachtungsstudie.

BACKGROUND: Within the framework of psychosomatic consultation in the workplace (PSIW), external expert psychotherapists offered consultation sessions for employees at the company premises in order to establish a first contact. In contrast to the first contact usually established in regular care, PSIW explicitly focuses on the workplace and enables in-company actors to get closely involved, if the patient's consent is provided. The new model of care helps to identify mental problems at an early stage and is clinically effective. Reliable data considering the user's point of view is missing. OBJECTIVES: How satisfied are users of the new model of care compared to users of regular care? MATERIAL AND METHODS: A total of 189 people from in-company (n = 91) or regular medical consultations (n = 98) made statements before first contact (t1) and 12 weeks (t2) after the initial contact. They reported satisfaction with the offer (t2), further treatment (t2), and depressiveness (t1, t2) by means of self-assessment tools. On the basis of an OLS (ordinary least squares) regression analysis, we investigated how treatment quality (clinical improvement, further treatment) and the place of treatment influenced user satisfaction (dependent variable), while controlling for selection bias and the different degrees of depression at baseline. RESULTS: Higher clinical improvement predicted more satisfaction with the received treatment in both (b = 1.2, CI 0.802-1.548). The mean value (MV) of satisfaction was 1.6 points higher if further treatment took place (CI 0.236-2.909). PSIW users showed a 1.8 points higher MV of satisfaction than people in regular care (CI 0.322-3.302). CONCLUSIONS: PSIW users consider PSIW as positive in terms of treatment success and service quality.

HDL functionality and cardiovascular outcome among nondialysis chronic kidney disease patients.

CVD remains the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD profoundly affects HDL composition and functionality, but whether abnormal HDL independently contributes to cardiovascular events in CKD patients remains elusive. In the present study, we assessed whether compositional and functional properties of HDL predict cardiovascular outcome among 526 nondialysis CKD patients who participate in the CARE FOR HOMe study. We measured HDL cholesterol, the content of HDL-associated proinflammatory serum amyloid A (SAA), and activities of the HDL enzymes paraoxonase and lipoprotein-associated phospholipase A2 (Lp-PLA2). In addition, we assessed the antioxidative activity of apoB-depleted serum. During a mean follow-up of 5.1 ± 2.1 years, 153 patients reached the predefined primary endpoint, a composite of atherosclerotic cardiovascular events including cardiovascular mortality and death of any cause. In univariate Cox regression analyses, lower HDL-cholesterol levels, higher HDL-associated SAA content, and lower paraoxonase activity predicted cardiovascular outcome, while Lp-PLA2 activity and antioxidative capacity did not. HDL-cholesterol and HDL-paraoxonase activity lost their association with cardiovascular outcome after adjustment for traditional cardiovascular and renal risk factors, while SAA lost its association after further adjustment for C-reactive protein. In conclusion, our data suggest that neither HDL quantity nor HDL composition or function independently predict cardiovascular outcome among nondialysis CKD patients.

Effects of endovascular cooling on infarct size in ST-segment elevation myocardial infarction: A patient-level pooled analysis from randomized trials.

OBJECTIVES: This study sought to examine the relationship between temperature at reperfusion and infarct size. BACKGROUND: Hypothermia consistently reduces infarct size when administered prior to reperfusion in animal studies, however, clinical results have been inconsistent. METHODS: We performed a patient-level pooled analysis from six randomized control trials of endovascular cooling during primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) in 629 patients in which infarct size was assessed within 1 month after randomization by either single-photon emission computed tomography (SPECT) or cardiac magnetic resonance imaging (cMR). RESULTS: In anterior infarct patients, after controlling for variability between studies, mean infarct size in controls was 21.3 (95%CI 17.4-25.3) and in patients with hypothermia <35°C it was 14.8 (95%CI 10.1-19.6), which was a statistically significant absolute reduction of 6.5%, or a 30% relative reduction in infarct size (P = 0.03). There was no significant difference in infarct size in anterior ≥35°C, or inferior infarct patients. There was no difference in the incidence of death, ventricular arrhythmias, or re-infarction due to stent thrombosis between hypothermia and control patients. CONCLUSIONS: The present study, drawn from a patient-level pooled analysis of six randomized trials of endovascular cooling during primary PCI in STEMI, showed a significant reduction in infarct size in patients with anterior STEMI who were cooled to <35°C at the time of reperfusion. The results support the need for trials in patients with anterior STEMI using more powerful cooling devices to optimize the delivery of hypothermia prior to reperfusion.

HDL structure and function is profoundly affected when stored frozen in the absence of cryoprotectants.

Analysis of structural and functional parameters of HDL has gained significant momentum in recent years because they are stronger predictors of cardiovascular risk than HDL-cholesterol levels. Surprisingly, in most HDL studies, very low attention is paid to HDL storage, which might critically affect functional properties. In the present study, we systematically examined the impact of storage and freezing on the structural/functional properties of freshly isolated HDL. Initial damage to HDL starts between week 1 and week 4 of storage. We observed that prolonged freezing at -20°C or -70°C led to a shedding of apoA-I from HDL and to the formation of large protein-poor particles, indicating that HDL is irreversibly disrupted. These structural alterations profoundly affected key metrics of HDL function, including HDL-cholesterol efflux capacity and HDL paraoxonase activity. Flash-freezing of isolated HDL prior to storage at -70°C did not preserve HDL structure. However, addition of the cryoprotectants, sucrose or glycerol, completely preserved structure and function of HDL when stored for at least 2 years. Our data clearly indicate that HDL is a complex particle requiring special attention when stored. Addition of cryoprotectants to isolated HDL samples before storage will make biochemical and clinical HDL research studies more reproducible and comparable.

Liver disease alters high-density lipoprotein composition, metabolism and function.

High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk.

Neutrophil effector responses are suppressed by secretory phospholipase A2 modified HDL.

Secretory phospholipase A2 (sPLA2) generates bioactive lysophospholipids implicated in acute and chronic inflammation, but the pathophysiologic role of sPLA2 is poorly understood. Given that high-density lipoprotein (HDL) is the major substrate for sPLA2 in plasma, we investigated the effects of sPLA2-mediated modification of HDL (sPLA2-HDL) on neutrophil function, an essential arm of the innate immune response and atherosclerosis. Treatment of neutrophils with sPLA2-HDL rapidly prevented agonist-induced neutrophil activation, including shape change, neutrophil extracellular trap formation, CD11b activation, adhesion under flow and migration of neutrophils. The cholesterol-mobilizing activity of sPLA2-HDL was markedly increased when compared to native HDL, promoting a significant reduction of cholesterol-rich signaling microdomains integral to cellular signaling pathways. Moreover, sPLA2-HDL effectively suppressed agonist-induced rise in intracellular Ca²âº levels. Native HDL showed no significant effects and removing lysophospholipids from sPLA2-HDL abolished all anti-inflammatory activities. Overall, our studies suggest that the increased cholesterol-mobilizing activity of sPLA2-HDL and suppression of rise in intracellular Ca²âº levels are likely mechanism that counteracts agonist-induced activation of neutrophils. These counterintuitive findings imply that neutrophil trafficking and effector responses are altered by sPLA2-HDL during inflammatory conditions.