Novel Associations Between Mid-Pregnancy Cardiovascular Biomarkers and Preeclampsia: An Explorative Nested Case-Control Study.

Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

AGPAT1 as a Novel Colonic Biomarker for Discriminating Between Ulcerative Colitis With and Without Primary Sclerosing Cholangitis.

INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC-UC) is considered a unique inflammatory bowel disease (IBD) entity. PSC diagnosis in an IBD individual entails a significantly higher risk of gastrointestinal cancer; however, biomarkers for identifying patients with UC at risk for PSC are lacking. We, therefore, performed a thorough PSC-UC biomarker study, starting from archived colonic tissue. METHODS: Proteins were extracted out of formalin-fixed paraffin-embedded proximal colon samples from PSC-UC (n = 9), UC (n = 7), and healthy controls (n = 7). Patients with IBD were in clinical and histological remission, and all patients with UC had a history of pancolitis. Samples were processed by the multienzyme digestion FASP and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Candidate proteins were replicated in an independent cohort (n: PSC-UC = 16 and UC = 21) and further validated by immunohistochemistry. RESULTS: In the discovery step, 7,279 unique proteins were detected. The top 5 most differentiating proteins (PSC-UC vs UC) based on linear regression analysis were selected for replication. Of these, 1-acetylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1) was verified as higher in PSC-UC than UC (P = 0.009) in the replication cohort. A difference on the group level was also confirmed by immunohistochemistry, showing more intense AGPAT1 staining in patients with PSC-UC compared with UC. DISCUSSION: We present AGPAT1 as a potential colonic biomarker for differentiating PSC-UC from UC. Our findings have possible implication for future PSC-IBD diagnostics and surveillance.

Impaired Fibrinolysis Predicts Adverse Outcome in Acute Coronary Syndrome Patients with Diabetes: A PLATO Sub-Study.

Hypofibrinolysis is a key abnormality in diabetes but the role of impaired clot lysis in predicting vascular events and mortality in this population is yet to be determined. We aimed to investigate the relationship between fibrin clot properties and clinical outcomes in patients with diabetes and recent acute coronary syndrome (ACS). Plasma samples were collected at hospital discharge from 974 ACS patients with diabetes randomised to clopidogrel or ticagrelor in the PLATO trial. A validated turbidimetric assay was employed to study fibrin clot lysis and maximum turbidity. One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were determined using Cox proportional analysis. After adjusting for CV risk factors, each 50% increase in lysis time was associated with increased risk of CV death/MI (HR 1.21; 95% confidence interval [CI] 1.02-1.44; p = 0.026) and CV death alone (HR 1.38; 1.08-1.76; p = 0.01). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death/MI (HR 1.25; 1.02-1.53; p = 0.031) and CV death alone (HR 1.49; 1.08-2.04; p = 0.014). The relationship between lysis time and the combined outcome of CV death and MI remained significant after adjusting for multiple prognostic vascular biomarkers (p = 0.034). Neither lysis time nor maximum turbidity was associated with major bleeding events. Impaired fibrin clot lysis predicts 1-year CV death and MI in diabetes patients following ACS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier NCT00391872.

Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study.

Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes. Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality. Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated. Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death. Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined. Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43). Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.

Does the Alpha-defensin Immunoassay or the Lateral Flow Test Have Better Diagnostic Value for Periprosthetic Joint Infection? A Meta-analysis.

BACKGROUND: Measuring alpha-defensin concentrations in synovial fluid may help to diagnose periprosthetic joint infection (PJI). There are two commercially available methods for measuring alpha-defensin in synovial fluid: the enzyme-linked immunosorbent assay-based Synovasure® alpha-defensin immunoassay, which gives a numeric readout within 24 hours, and the Synovasure lateral flow test, which gives a binary readout within 20 minutes. There is no compilation of the existing literature to support the use of one of these two tests over the other. QUESTIONS/PURPOSES: Does the immunoassay or the lateral flow test have better diagnostic value (sensitivity and specificity) in diagnosing PJI? METHODS: We followed PRISMA guidelines and identified all studies on alpha-defensin concentration in synovial fluid as a PJI diagnostic marker, indexed to April 14, 2017, in PubMed, JSTOR, Google Scholar, and OVID databases. The search retrieved 1578 records. All prospective and retrospective studies on alpha-defensin as a PJI marker (PJI classified according to the criteria of the Musculoskeletal Infection Society) after THA or TKA were included in the analysis. All studies used only one of the two commercially available test methods, but none of them was comparative. After excluding studies with overlapping patient populations, four studies investigating the alpha-defensin immunoassay and three investigating the lateral flow test remained. Alpha-defensin immunoassay studies included 482 joints and lateral flow test studies included 119. The quality of the trials was assessed according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The heterogeneity among studies was evaluated by the I index, indicating that the heterogeneity of the included studies was low. Pooled sensitivity, specificity, positive and negative likelihood ratios, and receiver operating curves were calculated for each method and compared with each other. RESULTS: The alpha-defensin immunoassay had superior overall diagnostic value compared with the lateral flow test (area under the curve, 0.98 versus 0.75) with higher sensitivity (96% [90%-98%] versus 71% [55%-83%], p < 0.001), but no difference in specificity with the numbers available (96% [93%-97%] versus 90% [81%-95%], p = 0.060). CONCLUSIONS: Measurement of alpha-defensin in synovial fluid is a valuable complement to existing diagnostic criteria, and the immunoassay test detects PJI more accurately than the lateral flow test. The lateral flow test has lower sensitivity, making it difficult to rule out infection, but its relatively high specificity combined with the advantage of a quick response time can make it useful to rule in infection perioperatively. LEVEL OF EVIDENCE: Level III, diagnostic study.

Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy.

Aims: To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS). Methods and results: Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events. Conclusion: Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

Antibodies against MYC-Associated Zinc Finger Protein: An Independent Marker in Acute Coronary Syndrome?

INTRODUCTION: Atherosclerosis is considered the pathophysiology underlying cardiovascular (CVD), cerebrovascular, and peripheral vascular diseases. Evidence supporting an autoimmune component is emerging, with imaging studies correlating MYC-associated zinc finger protein antibody (MAZ-Ab) optical density (OD) with plaque activity. This study compares MAZ-Ab OD on ELISA testing among patients presenting with acute coronary syndromes (ACSs) to healthy controls and investigates the association of MAZ-Ab to traditional CVD risk factors. METHODS: Patients admitted with ACSs between August 2007 and July 2011 were included. Serum samples taken at presentation were retrospectively tested for MAZ-Ab and compared with serum from healthy volunteers with no CVD risk factors. Large-scale assessment of post-ACS prognostic relevance was performed using the established PLATO cohort. RESULTS: In total 174 ACS patients and 96 controls were included. Among ACS patients, median MAZ-Ab OD was higher compared with controls (0.46 vs. 0.27; p = 0.001). Although the majority of ACS patients (116/174; 67%) had suffered from a ST-elevation myocardial infarction, no significant differences in MAZ-Ab titers were evident between ACS subtypes (p = 0.682). No associations between MAZ-Ab OD and conventional CVD risk factors were identified. Large-scale testing revealed no prognostic stratification regarding reinfarction (OR 1.04 [95% CI: 0.94-1.16]; p = 0.436). CONCLUSION: MAZ-Ab OD was higher or all ACS phenotypes compared with controls. Given current understanding of MAZ-Ab function, these findings support an autoimmune component to CVD independent of conventional risk factors and indeed the extent of end-organ damage.