Vaccine- and Breakthrough Infection-Elicited Pre-Omicron Immunity More Effectively Neutralizes Omicron BA.1, BA.2, BA.4 and BA.5 Than Pre-Omicron Infection Alone.

Since the emergence of SARS-CoV-2 Omicron BA.1 and BA.2, several Omicron sublineages have emerged, supplanting their predecessors. Here we compared the neutralization of Omicron sublineages BA.1, BA.2, BA.4 and BA.5 by human sera collected from individuals who were infected with the ancestral B.1 (D614G) strain, who were vaccinated (3 doses) or with breakthrough infection with pre-Omicron strains (Gamma or Delta). All Omicron sublineages exhibited extensive escape from all sera when compared to the ancestral B.1 strain and to Delta, albeit to different levels depending on the origin of the sera. Convalescent sera were unable to neutralize BA.1, and partly neutralized BA.2, BA.4 and BA.5. Vaccinee sera partly neutralized BA.2, but BA.1, BA.4 and BA.5 evaded neutralizing antibodies (NAb). Some breakthrough infections (BTI) sera were non-neutralizing. Neutralizing BTI sera had similar neutralizing ability against all Omicron sublineages. Despite similar levels of anti-Spike and anti-Receptor Binding Domain (RBD) antibodies in all groups, BTI sera had the highest cross-neutralizing ability against all Omicron sublineages and convalescent sera were the least neutralizing. Antibody avidity inferred from the NT50:antibody titer ratio was highest in sera from BTI patients, underscoring qualitative differences in antibodies elicited by infection or vaccination. Together, these findings highlight the importance of vaccination to trigger highly cross-reactive antibodies that neutralize phylogenetically and antigenically distant strains, and suggest that immune imprinting by first generation vaccines may restrict, but not abolish, cross-neutralization.

Pre-Omicron Vaccine Breakthrough Infection Induces Superior Cross-Neutralization against SARS-CoV-2 Omicron BA.1 Compared to Infection Alone.

SARS-CoV-2 variants raise concern because of their high transmissibility and their ability to evade neutralizing antibodies elicited by prior infection or by vaccination. Here, we compared the neutralizing abilities of sera from 70 unvaccinated COVID-19 patients infected before the emergence of variants of concern (VOCs) and of 16 vaccine breakthrough infection (BTI) cases infected with Gamma or Delta against the ancestral B.1 strain, the Gamma, Delta and Omicron BA.1 VOCs using live virus. We further determined antibody levels against the Nucleocapsid (N) and full Spike proteins, the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the Spike protein. Convalescent sera featured considerable variability in the neutralization of B.1 and in the cross-neutralization of different strains. Their neutralizing capacity moderately correlated with antibody levels against the Spike protein and the RBD. All but one convalescent serum failed to neutralize Omicron BA.1. Overall, convalescent sera from patients with moderate disease had higher antibody levels and displayed a higher neutralizing ability against all strains than patients with mild or severe forms of the disease. The sera from BTI cases fell into one of two categories: half the sera had a high neutralizing activity against the ancestral B.1 strain as well as against the infecting strain, while the other half had no or a very low neutralizing activity against all strains. Although antibody levels against the spike protein and the RBD were lower in BTI sera than in unvaccinated convalescent sera, most neutralizing sera also retained partial neutralizing activity against Omicron BA.1, suggestive of a better cross-neutralization and higher affinity of vaccine-elicited antibodies over virus-induced antibodies. Accordingly, the IC50: antibody level ratios were comparable for BTI and convalescent sera, but remained lower in the neutralizing convalescent sera from patients with moderate disease than in BTI sera. The neutralizing activity of BTI sera was strongly correlated with antibodies against the Spike protein and the RBD. Together, these findings highlight qualitative differences in antibody responses elicited by infection in vaccinated and unvaccinated individuals. They further indicate that breakthrough infection with a pre-Omicron variant boosts immunity and induces cross-neutralizing antibodies against different strains, including Omicron BA.1.

Relationship of oxidative stress to visceral adiposity in youth and role played by vitamin D.

BACKGROUND: Visceral adipose tissue (VAT) accumulation is a major cardiometabolic risk factor, associated with increased inflammation. Oxidative stress (OS) is also associated with inflammation and cardiometabolic issues, yet mainly through general obesity. Both OS and obesity were linked to vitamin D deficiency. OBJECTIVES: To investigate whether OS increase is associated with VAT accumulation in youth, and whether in the presence of VAT accumulation, a higher vitamin D status is associated with lower OS. METHODS: One hundred and fifty-eight youth with overweight/obesity, 7 to 17 years old, were recruited (Pediatric Clinic, Luxembourg). We assessed visceral and subcutaneous abdominal adipose tissues by magnetic resonance imaging, OS by DNA/RNA oxidative damage with ELISA and vitamin D by high-performance liquid chromatography. RESULTS: VAT was the body fat compartment the most strongly associated with OS (RPearson : 0.298; P < 10-4 ). The general linear (GLM) models assessing the relationship between OS, VAT and vitamin D concentrations showed that "Log10 OS = (0.003 × VAT) + 3.911 (R2adjusted : 0.083; P-value < 10-4 )"; "Log10 OS = (0.003 × VAT) - (0.156 × log10 vitamin D) + 4.110 (R2adjusted : 0.101; P-value < 10-4 )". After back-transformation of the log-values into normal values, the GLM showed that, for a person with an average value of VAT (40.7 cm2 ), a 10 cm2 increase in VAT would increase OS by approx. 771.833 pg/mL, after age, gender, Tanner stage and physical activity adjustment. An approximate increase of 9 ng/mL of vitamin D would counterbalance this negative effect of increased VAT. CONCLUSION: Dietary strategies improving vitamin D status should be investigated to tackle VAT and OS increase.

Protein S100 as outcome predictor after out-of-hospital cardiac arrest and targeted temperature management at 33 °C and 36 °C.

BACKGROUND: We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 °C and 36 °C) on serum levels of S100. METHODS: This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1-2 = good outcome, CPC 3-5 = poor outcome). RESULTS: We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10-0.49) versus 0.08 (IQR 0.06-0.11) µg/ml, 0.16 (IQR 0.10-0.44) versus 0.07 (IQR 0.06-0.11) µg/L, and 0.13 (IQR 0.08-0.26) versus 0.06 (IQR 0.05-0.09) µg/L (p < 0.001), respectively. The ability to predict outcome was best at 24 h with an AUC of 0.80 (95% CI 0.77-0.83). S100 values were higher at 24 and 72 h in the 33 °C group than in the 36 °C group (0.12 [0.07-0.22] versus 0.10 [0.07-0.21] µg/L and 0.09 [0.06-0.17] versus 0.08 [0.05-0.10], respectively) (p < 0.02). In multivariable analyses including baseline variables and the allocated target temperature, the addition of S100 improved the AUC from 0.80 to 0.84 (95% CI 0.81-0.87) (p < 0.001), but S100 was not an independent outcome predictor. Adding S100 to the same model including neuron-specific enolase (NSE) did not further improve the AUC. CONCLUSIONS: The allocated target temperature did not affect S100 to a clinically relevant degree. High S100 values are predictive of poor outcome but do not add value to present prognostication models with or without NSE. S100 measured at 24 h and afterward is of limited value in clinical outcome prediction after OHCA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01020916 . Registered on 25 November 2009.

Cardiometabolic risk: leg fat is protective during childhood.

BACKGROUND: Childhood obesity is associated with early cardiometabolic risk (CMR), increased risk of adulthood obesity, and worse health outcomes. Leg fat mass (LFM) is protective beyond total fat mass (TFM) in adults. However, the limited evidence in children remains controversial. OBJECTIVE: We investigated the relationship between LFM and CMR factors in youth. SUBJECTS: A total of 203 overweight/obese children, 7-17-yr-old, followed in the Pediatric Clinic, Luxembourg. METHODS: TFM and LFM by dual energy x-ray absorptiometry and a detailed set of CMR markers were analyzed. RESULTS: After TFM, age, sex, body mass index (BMI) Z-score, sexual maturity status, and physical activity adjustments, negative significant partial correlations were shown between LFM and homeostasis model assessment of insulin resistance (HOMA) (variance explained: 6.05% by LFM*; 7.18% by TFM**), fasting insulin (variance explained: 5.71% by LFM*; 6.97% by TFM**), triglycerides (variance explained: 3.96% by LFM*; 2.76% by TFM*), systolic blood pressure (variance explained: 2.68% by LFM*; 4.33% by TFM*), C-reactive protein (variance explained: 2.31% by LFM*; 4.28% by TFM*), and resistin (variance explained: 2.16% by LFM*; 3.57% by TFM*). Significant positive partial correlations were observed between LFM and high-density lipoprotein (HDL) cholesterol (variance explained: 4.16% by LFM*) and adiponectin (variance explained: 3.09% by LFM*) (*p-value < 0.05 and **p-value < 0.001). In order to adjust for multiple testing, Benjamini-Hochberg method was applied and the adjusted significance level was determined for each analysis. LFM remained significant in the aforementioned models predicting HOMA, fasting insulin, triglycerides, and HDL cholesterol (Benjamini and Hochberg corrected p-value < 0.01). CONCLUSIONS: LFM is protective against CMR in children, at least in terms of insulin resistance and adverse blood lipid profiles.

Adding anthropometric measures of regional adiposity to BMI improves prediction of cardiometabolic, inflammatory and adipokines profiles in youths: a cross-sectional study.

BACKGROUND: Paediatric research analysing the relationship between the easy-to-use anthropometric measures for adiposity and cardiometabolic risk factors remains highly controversial in youth. Several studies suggest that only body mass index (BMI), a measure of relative weight, constitutes an accurate predictor, whereas others highlight the potential role of waist-to-hip ratio (WHR), waist circumference (Waist C), and waist-to-height ratio (WHtR). In this study, we examined the effectiveness of adding anthropometric measures of body fat distribution (Waist C Z Score, WHR Z Score and/or WHtR) to BMI Z Score to predict cardiometabolic risk factors in overweight and obese youth. We also examined the consistency of these associations with the "total fat mass + trunk/legs fat mass" and/or the "total fat mass + trunk fat mass" combinations, as assessed by dual energy X-ray absorptiometry (DXA), the gold standard measurement of body composition. METHODS: Anthropometric and DXA measurements of total and regional adiposity, as well as a comprehensive assessment of cardiometabolic, inflammatory and adipokines profiles were performed in 203 overweight and obese 7-17 year-old youths from the Paediatrics Clinic, Centre Hospitalier de Luxembourg. RESULTS: Adding only one anthropometric surrogate of regional fat to BMI Z Score improved the prediction of insulin resistance (WHR Z Score, R(2): 45.9%. Waist C Z Score, R(2): 45.5%), HDL-cholesterol (WHR Z Score, R(2): 9.6%. Waist C Z Score, R(2): 10.8%. WHtR, R(2): 6.5%), triglycerides (WHR Z Score, R(2): 11.7%. Waist C Z Score, R(2): 12.2%), adiponectin (WHR Z Score, R(2): 14.3%. Waist C Z Score, R(2): 17.7%), CRP (WHR Z Score, R(2): 18.2%. WHtR, R(2): 23.3%), systolic (WHtR, R(2): 22.4%), diastolic blood pressure (WHtR, R(2): 20%) and fibrinogen (WHtR, R(2): 21.8%). Moreover, WHR Z Score, Waist C Z Score and/or WHtR showed an independent significant contribution according to these models. These results were in line with the DXA findings. CONCLUSIONS: Adding anthropometric measures of regional adiposity to BMI Z Score improves the prediction of cardiometabolic, inflammatory and adipokines profiles in youth.

A daily glass of red wine associated with lifestyle changes independently improves blood lipids in patients with carotid arteriosclerosis: results from a randomized controlled trial.

BACKGROUND: Physical exercise and a Mediterranean diet improve serum lipid profile. The present work studied whether red wine has an effect on top of a lipid-lowering lifestyle in patients with carotid atherosclerosis. METHODS: A prospective randomised unblinded trial was performed from 2009 to 2011 in 108 patients with carotid atherosclerosis, 65% of whom were already on statin therapy with a low mean LDL of 104.9 mg/dl. Half of them were advised to follow a modified Mediterranean diet and to perform moderate physical exercise during 30 min/day (lifestyle changes) for 20 weeks. Within these two groups half of the patients were randomised either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. RESULTS: LDL was significantly lowered by 7% in the lifestyle-changes group compared to the no-lifestyle-changes group (p = 0.0296) after 20 weeks. Lifestyle changes lowered the LDL/HDL ratio after 20 weeks by 8% (p = 0.0242) and red wine independently by 13% (p = 0.0049). The effect on LDL/HDL ratio after 20 weeks was, however, more pronounced in the non-LC group. Total cholesterol (-6%; p = 0.0238) and triglycerides (-13%; p = 0.0361) were lowered significantly by lifestyle changes after 20 weeks compared to the no-lifestyle-changes group. Lipoprotein (a) was not significantly affected by any intervention. The given results are per ITT analysis. CONCLUSIONS: Lifestyle changes including a modified Mediterranean diet and physical exercise as well as a glass of red wine daily improve independently the LDL/HDL ratio in patients with carotid arteriosclerosis even though the vast majority of them was already on statin therapy.

Use of circulating microRNAs to diagnose acute myocardial infarction.

BACKGROUND: Rapid and correct diagnosis of acute myocardial infarction (MI) has an important impact on patient treatment and prognosis. We compared the diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) and cardiac enriched microRNAs (miRNAs) in patients with MI. METHODS: Circulating concentrations of cardiac-enriched miR-208b and miR-499 were measured by quantitative PCR in a case-control study of 510 MI patients referred for primary mechanical reperfusion and 87 healthy controls. RESULTS: miRNA-208b and miR-499 were highly increased in MI patients (>10(5)-fold, P < 0.001) and nearly undetectable in healthy controls. Patients with ST-elevation MI (n= 397) had higher miRNA concentrations than patients with non-ST-elevation MI (n = 113) (P < 0.001). Both miRNAs correlated with peak concentrations of creatine kinase and cTnT (P < 10(-9)). miRNAs and hs-cTnT were already detectable in the plasma 1 h after onset of chest pain. In patients who presented <3 h after onset of pain, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients (P= 0.78). Overall, miR-499 and hs-cTnT provided comparable diagnostic value with areas under the ROC curves of 0.97. The reclassification index of miR-499 to a clinical model including several risk factors and hs-cTnT was not significant (P = 0.15). CONCLUSION: Circulating miRNAs are powerful markers of acute MI. Their usefulness in the establishment of a rapid and accurate diagnosis of acute MI remains to be determined in unselected populations of patients with acute chest pain.

Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients.

While immunopathology has been widely studied in patients with severe COVID-19, immune responses in non-hospitalized patients have remained largely elusive. We systematically analyze 484 peripheral cellular or soluble immune features in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 household controls. We observe a transient increase of IP10/CXCL10 and interferon-ß levels, coordinated responses of dominant SARS-CoV-2-specific CD4 and fewer CD8 T cells, and various antigen-presenting and antibody-secreting cells in mild patients within 3 days of PCR diagnosis. The frequency of key innate immune cells and their functional marker expression are impaired in hospitalized patients at day 1 of inclusion. T cell and dendritic cell responses at day 1 are highly predictive for SARS-CoV-2-specific antibody responses after 3 weeks in mild but not hospitalized patients. Our systematic analysis reveals a combinatorial picture and trajectory of various arms of the highly coordinated early-stage immune responses in mild COVID-19 patients.

Predicting significant fibrosis in hepatitis C patients in Luxembourg using serological markers.

OBJECTIVE: The aim of our study was to assess the diagnostic performance of various serological markers and scores for predicting significant fibrosis retrospectively in a population of patients referring to our hospital for liver biopsy and chronic hepatitis C. MATERIALS AND METHODS: Stored serum obtained from 186 patients were tested for a number of biological markers putatively associated with liver fibrosis. Fibrotest and Forns scores were compared with liver fibrosis pathology scored according to the METAVIR system by multiple logistic regression. RESULTS: The prevalence of significant fibrosis was 44%. Aspartate amino transferase (AST) and gamma-glutamyltransferase (GGT) were most correlated with METAVIR staging, followed by platelet counts and alpha2-macroglobulin. The negative predictive value was 77% and 83% and the positive predictive value was 100% and 84% for the Forns score and the Fibrotest, respectively. In multivariate analysis AST, GGT and alpha2-macroglobulin had independent predictive power. CONCLUSIONS: The accuracy of serological markers in predicting significant fibrosis is limited, because approximately two thirds of patients lie into an indeterminate "grey zone". Serological markers might be useful for patients reluctant to undergo liver biopsy but current predictive scoring systems are too inaccurate to replace biopsies in a routine manner.

Prevalence and Correlates of Vitamin D Deficiency and Insufficiency in Luxembourg Adults: Evidence from the Observation of Cardiovascular Risk Factors (ORISCAV-LUX) Study.

Evidence on vitamin D status and related risk factors in Luxembourg adults is lacking. This study aimed to determine the prevalence of vitamin D deficiency and insufficiency and related risk factors among healthy adults in Luxembourg. Based on clinicians' observations, it was hypothesized that vitamin D deficiency and insufficiency might be common in our population, constituting a significant public health concern. A nationally representative random sample of 1432 adults was enrolled in the ORISCAV-LUX study, 2007-2008. The participants were divided into four categories according to their serum concentrations of 25-hydroxyvitamin D [25(OH)D]. Descriptive, univariate and multivariate statistical analyses used weighted methods to account for the stratified sampling scheme. Only 17.1% of the population had a "desirable" serum 25(OH)D level ≥75 nmol/L, whereas 27.1% had "inadequate" [serum 25(OH)D level 50-74 nmol/L], 40.4% had "insufficient" [serum 25(OH)D level 25-49 nmol/L], and 15.5% had "deficient" [serum 25(OH)D level <25 nmol/L)]. The prevalence of vitamin D deficiency was greater among current smokers, obese subjects, those having reduced HDL-cholesterol level and fair/poor self-perception of health, compared to their counterparts. The prevalence of vitamin D insufficiency was additionally higher among nondrinkers of alcohol, Portuguese and subjects from non-European countries. The final multivariate logistic regression analyses revealed that smoking status and obesity were independent correlates of vitamin D deficiency and insufficiency, respectively. Inadequate vitamin D status is highly prevalent among adults in Luxembourg and is associated with specific lifestyle factors. Along with the effect of vitamin D deficiency and insufficiency on the risk of several diseases, cancer and mortality, our findings have practical implications for public health dietary recommendations, and of particular importance for healthcare practitioners and policy makers.

Neuron-Specific Enolase as a Predictor of Death or Poor Neurological Outcome After Out-of-Hospital Cardiac Arrest and Targeted Temperature Management at 33°C and 36°C.

BACKGROUND: Neuron-specific enolase (NSE) is a widely-used biomarker for prognostication of neurological outcome after cardiac arrest, but the relevance of recommended cutoff values has been questioned due to the lack of a standardized methodology and uncertainties over the influence of temperature management. OBJECTIVES: This study investigated the role of NSE as a prognostic marker of outcome after out-of-hospital cardiac arrest (OHCA) in a contemporary setting. METHODS: A total of 686 patients hospitalized after OHCA were randomized to targeted temperature management at either 33°C or 36°C. NSE levels were assessed in blood samples obtained 24, 48, and 72 h after return of spontaneous circulation. The primary outcome was neurological outcome at 6 months using the cerebral performance category score. RESULTS: NSE was a robust predictor of neurological outcome in a baseline variable-adjusted model, and target temperature did not significantly affect NSE values. Median NSE values were 18 ng/ml versus 35 ng/ml, 15 ng/ml versus 61 ng/ml, and 12 ng/ml versus 54 ng/ml for good versus poor outcome at 24, 48, and 72 h, respectively (p < 0.001). At 48 and 72 h, NSE predicted neurological outcome with areas under the receiver-operating curve of 0.85 and 0.86, respectively. High NSE cutoff values with false positive rates ≤5% and tight 95% confidence intervals were able to reliably predict outcome. CONCLUSIONS: High, serial NSE values are strong predictors of poor outcome after OHCA. Targeted temperature management at 33°C or 36°C does not significantly affect NSE levels. (Target Temperature Management After Cardiac Arrest [TTM]; NCT01020916).

Effects of different training modalities on circulating anabolic/catabolic markers in chronic heart failure.

BACKGROUND: Muscle wasting in chronic heart failure (CHF) is a result of increased catabolism induced by proinflammatory cytokines like tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), and decreased anabolism due to alterations in the insulin-like growth factor 1 (IGF-1)/growth hormone (GH) axis. The goal of this study was to analyze the effects of 3 different training modalities (endurance training, strength training, and combined strength and endurance training [CT]) on circulating cytokines, IGF-1, and GH levels. METHODS: Patients with CHF (N = 45), NYHA class II-III, left ventricular ejection fraction < 35%, were randomly assigned to 1 of 3 training modalities. They trained for 40 sessions, 3 times weekly. Fifteen CHF patients served as a control group. Blood samples were collected at baseline and 48 hours after the last training session. RESULTS: There was a significant decrease in circulating IL-6 with all 3 training modalities. Tumor necrosis factor α levels decreased in the training groups and reached statistical significance for the CT group. No change was observed in the control group. There was no difference between the 4 groups. When comparing all trained patients with the control group, the decrease in IL-6 was significant. Concerning IGF-1 and GH, there was no change with training and no change in the control group. CONCLUSION: Exercise training has no effects on circulating IGF-1 and GH. The decreases in cytokines are evident only when all trained patients are compared with the control group, independently of the modality of training intervention.

Modeling serum level of s100ß and bispectral index to predict outcome after cardiac arrest.

OBJECTIVES: This study was designed to evaluate multimodal prognostication in patients after cardiac arrest (CA). BACKGROUND: Accurate methods to predict outcome after CA are lacking. METHODS: Seventy-five patients with CA treated with therapeutic hypothermia after cardiac resuscitation were enrolled in this prospective observational study. Serum levels of neuron-specific enolase (NSE) and neuron-enriched S100 beta (S100ß) were measured 48 h after CA. Bispectral index (BIS) was continuously monitored during the first 48 h after CA. The primary endpoint was neurological outcome, as defined by the cerebral performance category (CPC) at 6-month follow-up: scores 1 or 2 indicated good outcome, and scores 3 to 5, poor outcome. The secondary endpoint was survival. RESULTS: A total of 46 (61%) patients survived at 6 months and 41 (55%) patients had CPC 1 or 2. Levels of NSE and S100ß were higher in patients with poor outcomes compared with patients with good outcomes (4-fold and 10-fold, respectively; p < 0.001). BIS was lower in patients with poor outcomes (10-fold; p < 0.001). NSE, S100ß, or BIS alone predicted neurological outcome, with areas under the receiver-operating characteristic curve (AUC) above 0.80. Combined determination of S100ß and BIS had an incremental predictive value (AUC: 0.95). S100ß improved discriminations based on BIS (p = 0.0008), and BIS improved discriminations based on S100ß (p < 10(-5)). Patients with S100ß level above 0.03 µg/l and BIS below 5.5 had a 3.6-fold higher risk of poor neurological outcome (p < 0.0001). S100ß and BIS predicted 6-month mortality (log-rank statistic: 50.41; p < 0.001). CONCLUSIONS: Combined determination of serum level of S100ß and BIS monitoring accurately predicts outcome after CA.

MicroRNAs in patients on chronic hemodialysis (MINOS study).

BACKGROUND AND OBJECTIVES: Diagnosis of acute myocardial injury with biomarkers is difficult in patients with advanced renal failure. Circulating microRNAs are promising new biomarkers of myocardial injury. It is unknown whether levels of microRNAs are affected in patients undergoing hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: High-sensitivity cardiac troponin T (hsTnT) and cardiac-enriched miR-499 were measured in 41 patients with ESRD undergoing hemodialysis and 41 controls. RESULTS: Levels of hsTnT and miR-499 were highly elevated in patients with ESRD compared with controls (>80-fold increase; P<0.001). Among patients with ESRD, 98% had positive hsTnT levels and 46% had positive miR-499 levels. Levels of troponins were not affected by hemodialysis. However, miR-499 levels were decreased after hemodialysis (6.5-fold decrease; P=0.002). CONCLUSIONS: Both miR-499 and troponins are elevated in patients with advanced renal failure. However, whereas levels of troponins are unaffected by hemodialysis, this is not the case for miR-499. Therefore, these observations mitigate the potential of miR-499 as a marker of myocardial injury in patients with ESRD.

Assessment of procalcitonin to predict outcome in hypothermia-treated patients after cardiac arrest.

Objective. Determine the potential of procalcitonin (PCT) to predict neurological outcome after hypothermia treatment following cardiac arrest. Methods. Retrospective analysis of patient data over a 2-year period. Mortality and neurological outcome of survivors were determined 6 months after cardiac arrest using the Cerebral Performance Category (CPC) score. Results. Data from 53 consecutive patients were analyzed. Median age was 63 (54-71) and 79% were male. Twenty-seven patients had good outcome (CPC ≤ 2) whereas 26 had severe neurological sequelae or died (CPC 3-5). At 48 h, after regaining normothermia, PCT was significantly higher in patients with bad outcome compared to those with good outcome: 3.38 (1.10-24.48) versus 0.28 (0-0.75) ng/mL (P < 0.001). PCT values correlated with bad neurological outcome (r = 0.54, P = 0.00004) and predicted outcome with an area under the curve of 0.84 (95% CI 0.73-0.96). A cutoff point of 1 ng/mL provided a sensitivity of 85% and a specificity of 81%. Above a PCT level of 16 ng/mL, no patient regained consciousness. PCT provided an additive value over simplified acute physiology score II. Conclusions. PCT might be an ancillary marker for outcome prediction after cardiac arrest treated by induced hypothermia.

Proteomic analysis of plasma samples from patients with acute myocardial infarction identifies haptoglobin as a potential prognostic biomarker.

Prognosis of clinical outcome following myocardial infarction is variable and difficult to predict. We have analyzed the plasma proteome of thirty patients with acute myocardial infarction to search for new prognostic biomarkers. Proteomic analyses of blood samples were performed by 2-D-DiGE after plasma depletion of albumin and immunoglobulins G. New York Heart Association (NYHA) class determined at 1-year follow-up was used to identify patients with heart failure. Principal component analysis and hierarchical clustering of proteomic data revealed that patients could be separated into 3 groups. The 22 differentially expressed proteins involved in this grouping were identified as haptoglobin (Hp) and respective isoforms. The 3 groups of patients had distinct Hp isoforms: patients from group 1 had the α1-α1, patients from group 2 the α2-α1, and patients from group 3 the α2-α2 genotype. This classification was also associated with different total plasma levels of Hp. The presence of the α2 genotype and low plasma levels of Hp was associated with a higher NYHA class and therefore with a detrimental functional outcome after myocardial infarction. A plasma level of Hp below 1.4g/L predicted the occurrence of heart failure (NYHA 2, 3, 4) at 1-year with 100% sensitivity.

Relationship between pulse transit time and blood pressure is impaired in patients with chronic heart failure.

AIMS: Pulse transit time (PTT), the interval between ventricular electrical activity and arrival of the peripheral pulse wave, has been used to detect changes in autonomic tone during sleep and anesthesia. The purpose of this study was to evaluate PTT in patients with chronic heart failure (HF). METHODS AND RESULTS: Pulse transit time was measured with R-wave gated photoplethysmography in 24 healthy volunteers and in 112 patients with chronic HF and ejection fraction (EF) <40%. PTT was mildly elevated in patients with HF (468 ± 12 vs. 430 ± 23 ms, p = 0.001). In healthy volunteers, PTT was directly proportional to blood pressure (BP): when BP increased, PTT shortened, and vice versa. This relationship between PTT and BP (PTTi) was altered in patients with HF and particularly in the 26 patients with decompensated HF (3.6 ± 0.4 vs. 4.2 ± 0.9, p = 0.04). PTTi did not correlate with functional NYHA class and levels of pro-BNP, epinephrine or norepinephrine. There was a modest correlation between PTTi and EF (p = 0.01, r = -0.48) and PTTi tended to correlate with microvascular flow measured with Laser Doppler (p = 0.08). However, there was an excellent correlation between PTTi and systolic time intervals, left ventricular ejection time (LVET) (p = 0.0014, r = -0.75) and pre-ejection time/LVET (p = 0.006, r = 0.80). The latter ratio reflects ventricular-arterial coupling. CONCLUSION: The relationship between PTT and BP is altered in severe HF and may indicate impaired ventricular-arterial coupling. It merits further investigation as both parameters can be easily determined and used for serial monitoring in HF.

Reverse remodelling through exercise training is more pronounced in non-ischemic heart failure.

PURPOSE: Most training studies in patients with chronic heart failure (CHF) do not consider CHF aetiology in the interpretation of the results. About 60% of the patients in those studies have ischemic CHF (IHF) and 40% non-ischemic CHF (NHF). Recently, we conducted a randomized controlled trial to study three different training modalities in 60 patients with severe CHF, with a similar distribution of IHF and NHF patients. In the present post hoc analysis we compared the differences in training results between ischemic and non-ischemic patients. METHODS: Left ventricular ejection fraction (EF), end diastolic volume (EDV), end systolic volume (ESV), measured with radionuclide ventriculography (RNV) and echocardiography, NT-pro BNP, peak oxygen uptake (peak V(O)(2)), working capacity and muscular volume were analyzed before and after training in 45 patients training for 40 sessions, 3 times per week. Fifteen patients served as control group. The outcome was analyzed considering the aetiology of CHF, either ischemic or non-ischemic. RESULTS: There were no significant differences in improvements of peak V(O)(2), working capacity and muscular volume between IHF and NHF patients. In NHF patients, EF increased while EDV and ESV decreased after training. These parameters remained unchanged in IHF patients after training. NT-pro BNP decreased significantly in NHF patients and increased in IHF patients after training. In the control group, patients showed a mild improvement of EF and a decrease of NT-pro BNP. CONCLUSION: This post hoc analysis shows that training intervention is associated with significant reverse remodelling in NHF, but not in IHF patients, whereas V(O)(2) peak and muscle volume improve regardless of CHF aetiology. Future prospective studies are needed to confirm our findings.