An application of the patient rule-induction method for evaluating the contribution of the Apolipoprotein E and Lipoprotein Lipase genes to predicting ischemic heart disease

Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions. Genet. Epidemiol . 2007. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56137/1/20225_ftp.pd

Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study

Objective To test the hypothesis that xanthelasmata and arcus corneae, individually and combined, predict risk of ischaemic vascular disease and death in the general population

Gender- and age-specific contributions of additional DNA sequence variation in the 5′ regulatory region of the APOE gene to prediction of measures of lipid metabolism

In the present study of 9,000 individuals representative of the general population, we have considered whether the addition of common single nucleotide polymorphisms (SNPs) in the promoter region of Apolipoprotein E ( APOE ) improve the statistical explanation of variation in lipid traits and test the hypothesis that the estimated genotype effects are independent of factors indexed by gender and age. To address these questions, we have asked, for each gender and for each 20-year age strata (young: 20–39 years; middle-aged: 40–59 years; old: 60–79 years; very old: 80–100 years), how much trait variation is associated with the traditional ε2, ε3, and ε4 allelic variations defined by the g.2059T→C and g.2197C→T SNPs in the fourth exon of the APOE gene, and how much additional trait variation is associated with genotypes defined by combining the g.2059T→C and g.2197C→T SNPs with one, two, or three promoter SNPs. Our study demonstrates that the pleiotropic effects of genotype variation defined by the traditional ε2, ε3, and ε4 alleles on five plasma measures of lipid metabolism manifest differently in women and men and change significantly during the life cycle for high-density lipoprotein cholesterol in women. Multi-site genotypes defined by adding SNPs located in the 5′ promoter region to the traditional g.2059T→C and g.2197C→T SNPs doubled the estimate of genetic variance of high-density lipoprotein and apolipoprotein Al in middle-aged females.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47594/1/439_2004_Article_1165.pd

Inflammatory response after prehospital high-dose glucocorticoid to patients resuscitated from out-of-hospital cardiac arrest:A sub-study of the STEROHCA trial

Background: The post-cardiac arrest syndrome (PCAS) after out-of-hospital cardiac arrest (OHCA) is characterized by a series of pathological events, including inflammation. In the randomized “STERoid for OHCA” (STEROHCA) trial, prehospital high-dose glucocorticoid decreased interleukin (IL) 6 and C-reactive protein levels following resuscitated OHCA. The aim of this predefined sub-study was to assess the inflammatory response the first three days of admission. Methods: The STEROHCA trial enrolled 137 OHCA patients randomized to either a single prehospital injection of methylprednisolone 250 mg or placebo. Inflammatory markers, including pro- and anti-inflammatory cytokines, were analyzed in plasma samples, from 0-, 24-, 48-, and 72 h post-admission. Mixed-model analyses were applied using log-transformed data to assess group differences. Results: The 137 patients included in this sub-study had a median age of 67 years (57 to 74), and the 180-day survival rates were 75% (n = 51/68) and 64% (n = 44/69) in the glucocorticoid and placebo group, respectively. A total of 130 (95%) patients had at least one plasma sample available. The anti-inflammatory cytokine IL-10 was increased at hospital admission in the glucocorticoid group (ratio 2.74 (1.49–5.05), p = 0.006), but the intervention showed the strongest effect after 24 h, decreasing pro-inflammatory levels of IL-6 (ratio 0.06 (0.03–0.10), p &lt; 0.001), IL-8 (ratio 0.53 (0.38–0.75), p &lt; 0.001), macrophage chemokine protein-1 (MCP-1, ratio 0.02 (0.13–0.31), p &lt; 0.001), macrophage inflammatory protein-1-beta (MIP-1b, ratio 0.28 (0.18–0.45), p &lt; 0.001), and tumor necrosis factor-α (TNF-α, ratio 0.6 (0.4–0.8), p = 0.01). Conclusion: Administering high-dose glucocorticoid treatment promptly after resuscitation from OHCA influenced the inflammatory response with a reduction in several systemic proinflammatory cytokines after 24 h. Trial registration: EudraCT number: 2020–000855-11; submitted March 30, 2020. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04624776.</p

Effects of Atrial Fibrillation Screening According to N-Terminal Pro-B-Type Natriuretic Peptide:a Secondary Analysis of the Randomized LOOP Study

Background: Research suggests NT-proBNP (N-terminal pro-B-type natriuretic peptide) to be a strong predictor of incident atrial fibrillation (AF) and stroke. However, its utility in AF screening remains unknown. The aim of this study was to investigate NT-proBNP as a potential marker for screening efficacy with respect to AF yield and stroke prevention. Methods: In the LOOP Study (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals), 6004 AF-naïve individuals at least 70 years old and with additional stroke risk factors were randomized 1:3 to either screening with an implantable loop recorder (ILR) and initiation of anticoagulation upon detection of AF episodes lasting ≥6 minutes or usual care (control). This post hoc analysis included study participants with available NT-proBNP measurement at baseline. Results: A total of 5819 participants (96.9% of the trial population) were included. The mean age was 74.7 years (SD, 4.1 years) and 47.5% were female. The median NT-proBNP level was 15 pmol/L (interquartile range, 9-28 pmol/L) corresponding to 125 pg/mL (interquartile range, 76-233 pg/mL). NT-proBNP above median was associated with an increased risk of AF diagnosis both in the ILR group (hazard ratio, 1.84 [95% CI, 1.51-2.25]) and the control group (hazard ratio, 2.79 [95% CI, 2.30-3.40]). Participants with NT-proBNP above the median were also at higher risk of clinical events compared with those having lower levels (hazard ratio, 1.21 [95% CI, 0.96-1.54] for stroke or systemic embolism [SE], 1.60 [95% CI, 1.32-1.95] for stroke/SE/cardiovascular death, and 1.91 [95% CI, 1.61-2.26] for all-cause death). Compared with usual care, ILR screening was associated with significant reductions in stroke/SE and stroke/SE/cardiovascular death among participants with NT-proBNP above median (hazard ratio, 0.60 [95% CI, 0.40-0.90] and 0.70 [95% CI, 0.53-0.94], respectively) but not among those with lower levels (P interaction=0.029 for stroke/SE and 0.045 for stroke/SE/cardiovascular death). No risk reduction in all-cause death was observed in either NT-proBNP subgroup for ILR versus control (P interaction=0.68). Analyzing NT-proBNP as a continuous variable yielded similar findings. Conclusions: In an older population with additional stroke risk factors, ILR screening for AF was associated with a significant reduction in stroke risk among individuals with higher NT-proBNP levels but not among those with lower levels. These findings should be considered hypothesis generating and warrant further study before clinical implementation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450.</p

Neurofilament light chain for prognostication after cardiac arrest-first steps towards validation

Background: After cardiac arrest, many patients remain comatose, and a substantial proportion do not survive. Neuroprognostication is essential for identifying patients with potential for recovery, and those with severe, irreversible hypoxic-ischemic brain injury. Neurofilament light chain (NfL) is a blood-based marker of neuronal injury that is under evaluation for neuroprognostication. NfL have potential advantages over the currently only guideline recommended blood biomarker for neuroprognostication, neuron-specific enolase, including earlier applicability. However, there is no consensus on optimal NfL cut-off levels. A previous large investigation in OHCA patients, identified NfL thresholds with high specificity for poor outcome, and the purpose of the present investigation is to validate these cutoffs. Methods: The Blood Pressure and Oxygenation Targets in Post Resuscitation Care (BOX) trial included OHCA patients who were comatose at admission. Patients with at least one plasma biobank sample available at 24–48 h were included in this investigation. NfL was quantified by ELISA. Cerebral performance category score was estimated at 1 year. Diagnostic precision of NfL for prediction of poor neurologic outcome (CPC &gt; 2) was determined by area under the receiver operator curve (AUROC), and the performance of previously identified cut-offs for a specificity of 100% were investigated. Results: A total of 638 patients had a NfL measurement at either 24 or 48 h. The AUROC for prediction of poor neurologic outcome was 0.95 and 0.95 at 24 and 48 h, respectively. At 24 h, a cut-off of 1232 pg/mL had a specificity of 98%, for prediction of poor neurologic outcome, and false-positive results for 7 patients (1.4%). At 48 h, a cut-off of 1539 pg/ml similarly had a specificity of 98%, and false-positive results for 7 patients (1.3%). Conclusions: The results of this investigation confirm the prognostic value of NfL for identification of risk of poor neurologic outcome after cardiac arrest. Previously identified cut-offs of 1232 pg/mL at 24 h, and 1539 pg/mL at 48 h, performed excellent with a very high specificity. This indicates that application of NfL will allow for reliable neuroprognostication as early as 24 h after cardiac arrest. Trial registration: ClinicalTrials.gov</p