Paulene A. Quinn

C-Terminal Provasopressin (Copeptin) as a Novel and Prognostic Marker in Acute Myocardial Infarction. Leicester Acute Myocardial Infarction Peptide (LAMP) Study

Background— The role of the vasopressin system after acute myocardial infarction is unclear. Copeptin, the C-terminal part of the vasopressin prohormone, is secreted stoichiometrically with vasopressin. We compared the prognostic value of copeptin and an established marker, N-terminal pro-B-type natriuretic peptide (NTproBNP), after acute myocardial infarction. Methods and Results— In this prospective single-hospital study, we recruited 980 consecutive post–acute myocardial infarction patients (718 men, median [range] age 66 [24 to 95] years), with follow-up over 342 (range 0 to 764) days. Plasma copeptin was highest on admission (n=132, P<0.001, day 1 versus days 2 to 5) and reached a plateau at days 3 to 5. In the 980 patients, copeptin (measured at days 3 to 5) was elevated in patients who died (n=101) or were readmitted with heart failure (n=49) compared with survivors (median [range] 18.5 [0.6 to 441.0] versus 6.5 [0.3 to 267.0] pmol/L, P<0.0005). With logistic regression analysis, copeptin (odds ratio, 4.14, P<0.0005) and NTproBNP (odds ratio, 2.26, P<0.003) were significant independent predictors of death or heart failure at 60 days. The area under the receiver operating characteristic curves for copeptin (0.75) and NTproBNP (0.76) were similar. The logistic model with both markers yielded a larger area under the curve (0.84) than for NTproBNP (P<0.013) or copeptin (P<0.003) alone, respectively. Cox modeling predicted death or heart failure with both biomarkers (log copeptin [hazard ratio, 2.33], log NTproBNP [hazard ratio, 2.70]). In patients stratified by NTproBNP (above the median of ≈900 pmol/L), copeptin above the median (≈7 pmol/L) was associated with poorer outcome (P<0.0005). Findings were similar for death and heart failure as individual end points. Conclusions— The vasopressin system is activated after acute myocardial infarction. Copeptin may predict adverse outcome, especially in those with an elevated NTproBNP (more than ≈900 pmol/L).

C-Terminal Provasopressin (Copeptin) is Associated With Left Ventricular Dysfunction, Remodeling, and Clinical Heart Failure in Survivors of Myocardial Infarction

BACKGROUND Acute myocardial infarction (AMI) is associated with left ventricular (LV) dysfunction and clinical heart failure. Arginine vasopressin is elevated in heart failure and the C-terminal of provasopressin (Copeptin) is associated with adverse outcome post-AMI. The aim of this study was to describe the association between Copeptin with LV dysfunction, volumes, and remodeling and clinical heart failure post-AMI. METHODS AND RESULTS We studied 274 subjects with AMI. Copeptin was measured from plasma at discharge and subjects underwent echocardiography at discharge and follow-up (median 155 days). Subjects were followed for clinical heart failure for a median of 381 days. Remodeling was assessed as the change (Delta) in LV volumes between echo examinations. Copeptin correlated directly with wall motion index score (WMIS) and inversely with LV ejection fraction (LVEF) at discharge (WMIS, r=0.276, P < .001; LVEF, r=-0.188, P=.03) and follow-up (WMIS, r=0.244, P < .001; LVEF, r=-0.270, P < .001) and with ventricular volumes at follow-up (LVEDV, r=0.215, P=.002; LVESV, r=0.299, P < .001). Copeptin was associated with ventricular remodeling; DeltaEDV; r=0.171, P=0.015, DeltaESV; r=0.186, P=.008. Subjects with increasing LVESV had higher levels of Copeptin (median 6.30 vs. 5.75 pmol/L, P=.012). Subjects with clinical heart failure (n=30) during follow-up had higher Copeptin before discharge (median 13.55 vs. 5.80, P < .001). In a Cox proportional hazards model, Copeptin retained association with clinical heart failure. Kaplan-Meier assessment revealed increased risk in subjects with Copeptin >6.31 pmol/L. CONCLUSIONS Copeptin is associated with LV dysfunction, volumes, and remodeling and clinical heart failure post-AMI. Measurement of Copeptin may provide prognostic information and the AVP system may be a therapeutic target in post-MI LV dysfunction.

Myeloperoxidase aids prognostication together with N-terminal pro-B-type natriuretic peptide in high-risk patients with acute ST elevation myocardial infarction

Background: Inflammation plays a critical role in acute myocardial infarction (MI). One such inflammatory marker is myeloperoxidase (MPO). Its role as a predictor of death or MI in patients with ST segment elevation myocardial infarction (STEMI) is unclear. Aim: To investigate the role of MPO as a predictor of death or MI in patients with STEMI and to compare it with N-terminal pro-B-type natriuretic peptide (NT-BNP). Method: 384 post STEMI patients were studied. Patients were followed up for the combined end point of death or readmission with non-fatal MI. Results: There were 40 deaths and 37 readmissions with MI. Median MPO was raised in patients experiencing death or MI than in survivors (median (range), 50.6 (15.3–124.1) ng/ml vs 33.5 (6.6–400.2) ng/ml, p = 0.001). Using a Cox proportional hazards model, log median MPO (HR 6.91, 95% CI 1.79 to 26.73, p = 0.005) and log median NT-BNP (HR 4.21, 95% CI 1.53 to 11.58, p = 0.005) independently predicted death or non-fatal MI. MPO had predictive power in both below and above median NT-BNP levels (log rank 5.60, p = 0.020 and log rank 5.12, p = 0.024, respectively). The receiver-operating curve for median NT-BNP yielded an area under the curve (AUC) of 0.72 (95% CI 0.65 to 0.79, p<0.001); for median MPO, the AUC was 0.62 (95% CI 0.55 to 0.69, p = 0.001). The logistic model combining the two markers yielded an AUC of 0.76 (95% CI 0.69 to 0.82, p<0.001). Conclusion: MPO and NT-BNP may be useful tools for risk stratification of all acute coronary syndromes, including patients with STEMI at higher risk.

Plasma N-terminal B-Type natriuretic peptide as an indicator of long-term survival after acute myocardial infarction: comparison with plasma midregional pro-atrial natriuretic peptide: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.

OBJECTIVES Our aim was to assess the prognostic value of midregional pro-atrial natriuretic peptide (MR-proANP) in patients after acute myocardial infarction (AMI). BACKGROUND Multimarker strategies may assist risk stratification after AMI. Midregional pro-atrial natriuretic peptide is a newly described stable fragment of N-terminal pro-atrial natriuretic peptide. We compared the prognostic value of MR-proANP and an established marker, N-terminal pro-B-type natriuretic peptide (NT-proBNP), after AMI. METHODS We recruited 983 consecutive post-AMI patients (720 men, median age 65 [range 24 to 95] years) in a prospective study with follow-up over 343 (range 0 to 764) days. RESULTS Plasma MR-proANP was raised in patients who died (n = 101) compared with that seen in survivors (median 310 [range 48 to 1,150] pmol/l vs. 108 [range 4.9 to 1,210] pmol/l, p < 0.0001). Using Cox modeling, log(10)MR-proANP (hazard ratio 3.87) and log(10)NT-proBNP (hazard ratio 3.25) were significant independent predictors of death. In patients stratified by NT-proBNP in the highest quartile (> approximately 5,900 pmol/l), MR-proANP in the top quartile ( approximately 330 pmol/l) was associated with poorer outcome (p < 0.0001). Findings were similar for heart failure as an individual end point. However, neither marker predicted recurrent AMI. CONCLUSIONS The A- and B-type natriuretic systems are activated after AMI. Midregional pro-atrial natriuretic peptide is a powerful predictor of adverse outcome, especially in those with an elevated NT-proBNP. Midregional pro-atrial natriuretic peptide may represent a clinically useful marker of prognosis after an AMI as part of a multimarker strategy targeting the natriuretic neurohormonal pathway.

Advanced Glycation End Products Stimulate an Enhanced Neutrophil Respiratory Burst Mediated Through the Activation of Cytosolic Phospholipase A2 and Generation of Arachidonic Acid

Background—Advanced glycation end products (AGEs) enhance NADPH oxidase, and hence respiratory burst activity, of stimulated neutrophils. They are thus potentially vasculopathic, especially in diabetes, uremia, and aging, in which AGEs classically accumulate. We investigated the underlying mechanisms. Methods and Results—Neutrophils prelabeled with [3H]arachidonic acid display increased [3H]arachidonate release on exposure to AGE-albumin over exposure to albumin alone (by 151±16%, P <0.01). Arachidonic acid (AA) itself seems to mediate the AGE-augmented neutrophil respiratory burst (ascertained by chemiluminescence). Inhibitors of the cyclooxygenase pathway (indomethacin) and lipoxygenase pathway (MK-886) do not impair this AGE effect, excluding a contribution from AA metabolites. Cytosolic phospholipase A2 (cPLA2) controls AA generation. Its inhibition by methyl arachidonyl fluorophosphonate abrogates the AGE-enhanced activated neutrophil respiratory burst, and it is demonstrably stimulated in AGE-exposed neutrophils, as evidenced by isoform gel-shift and an increasingly membrane-translocated state in Western blots of neutrophil subfractions. Inhibition of other PLA2 isoforms, secretory PLA2 and calcium-independent PLA2, by manoalide and haloenol-lactone suicide substrate, respectively, does not affect this effect of AGEs relative to inhibitor-treated controls. The thiol antioxidant NAC reduces activation of cPLA2 (assessed by isoform gel-shift and membrane translocation), production of AA in AGE-albumin–exposed neutrophils (H3 release reduced to 104±17%, P =0.94 compared with albumin-exposed neutrophils), and the AGE-augmented neutrophil respiratory burst. Conclusions—AGE augmentation of the activated neutrophil respiratory burst requires AA generation, through which neutrophil NADPH oxidase may be upregulated, enhancing reactive oxygen species output. AA is generated by cPLA2, which may be stimulated through an AGE-activated redox-sensitive pathway.

Interleukin 33 and ST2 in non–ST-elevation myocardial infarction: Comparison with Global Registry of Acute Coronary Events Risk Scoring and NT-proBNP

BACKGROUND Soluble ST2 is a marker of biomechanical strain for which the natural ligand is interleukin 33 (IL-33). They have not been studied together in non-ST-elevation myocardial infarction (NSTEMI). We investigated their relationship with death, heart failure (HF) readmission, and reinfarction combined (termed major adverse cardiac events [MACE]) and, separately, in unselected patients using Global Registry of Acute Coronary Events Risk Scoring (GRACE-RS) and n terminal pro B type natriuretic peptide (NT-proBNP) as benchmark comparators. METHODS ST2 and IL-33 were measured in 577 patients 3 to 5 days after admission. Mean follow-up was 532 (150-1059) days, during which 156 patients (27%) reached the primary end point. RESULTS ST2 was higher in those who experienced MACE when compared with event-free survivors (median 782 pg/mL vs 596, P < .001), but there was no difference in IL-33 levels across any end point. Multivariate Cox regression analysis reveals that elevated ST2 is independently associated with increased risk of MACE during the long term (hazard ratio [HR] 2.01, P = .005). This relationship continues on further adjustment for either GRACE risk score or NT-proBNP individually but not on adjustment for both. ST2 also independently predicts reinfarction (HR 2.48, P = .03) and 30-day mortality (HR 4.43, P = .02, c-statistic 0.73, P < .001). Adding ST2 to GRACE or to NT-proBNP did not lead to significant improvements in the c-statistic for MACE for long-term follow-up (P = .27 and P = .57, respectively) or the net reclassification index. Neither IL-33 nor its ratio with ST2 was associated with study end points. CONCLUSIONS Elevated ST2 predicts adverse outcome in non-ST-elevation myocardial infarction but does not significantly improve risk stratification for established markers. Interleukin 33 was not related to adverse events.

N-terminal pro-B-type natriuretic peptide is better than TIMI risk score at predicting death after acute myocardial infarction

Background: The TIMI risk score is a well-validated scoring system used to predict mortality in patients following an ST-segment elevation myocardial infarction (STEMI). N-terminal pro-B-type natriuretic peptide (NTproBNP) has also been found to be useful in predicting mortality following STEMI. Objective: To investigate the utility of the TIMI score and NTproBNP levels at predicting risk of death in patients with acute myocardial infarction (AMI). Methods: 473 patients (352 men, mean (SD) age 63.7 (12.3) years) with AMI were studied. Blood was drawn within 24 hours after the onset of chest pain and the plasma concentration of NTproBNP was determined using an in-house non-competitive immunoassay. Patients’ TIMI risk score was measured and patients stratified into low- (0 to 2), intermediate- (3–7) and high-risk (>8) groups. Results: Mortality was 8.9% and was related to higher TIMI risk scores (p = 0.029 for trend). Higher NTproBNP levels were also related to increased mortality (median (range) fmol/ml, survivors 700.2 (0.3–11485.3) vs dead 5781.3 (1.4–10835.9), p<0.001). In a multivariate binary logistic regression model, independent predictors of mortality were NTproBNP levels in the first 24 hours (odds ratio (OR) = 4.21, 95% CI 1.96 to 9.07, p<0.001) together with drug treatments. The receiver operating curve for NTproBNP in the first 24 hours yielded an area under the curve (AUC) of 0.79 (95% CI 0.70 to 0.88), p<0.001, for TIMI risk score the AUC was 0.67 (95% CI 0.58 to 0.76), p = 0.001. Conclusion: In the first 24 hours following an AMI, NTproBNP is better than the TIMI risk score at predicting mortality. A simple NTproBNP blood test is more easily applicable and is more accurate than a clinical risk score.

NADPH Oxidase Activity in Preeclampsia With Immortalized Lymphoblasts Used as Models

Abstract—Upon activation, neutrophils release reactive oxygen species that are believed to contribute to the widespread manifestation of preeclampsia. Neutrophils have an NADPH oxidase enzyme that catalyzes the production of reactive oxygen species. Little is known about the manifestations of the activated response and the upstream signaling pathways that regulate this process in preeclampsia. It is hypothesized that genetic factors may contribute to the release of reactive oxygen species and consequently the pathophysiology of the disease. We used Epstein-Barr virus–immortalized lymphoblasts from third-trimester, preeclamptic, postpartum preeclamptic women and their respective control subjects to assess NADPH oxidase–mediated reactive oxygen species production by using luminol-derived chemiluminescence and dihydrorhodamine-123 fluorescence. There was no effect of pregnancy status on the lymphoblast phorbol ester–stimulated luminol chemiluminescence area under the curve. However, lymphoblasts from preeclamptic patients had significant elevation of the lymphoblast phorbol ester–stimulated luminol area under the curve (F statistic 10.922, P <0.002). Similar findings were evident with dihydrorhodamine-123. No differences were revealed between preeclamptic and control cells when measuring the abundance of the phox proteins using Western blotting. Studies with genistein and tyrphostin implicated tyrosine kinase–dependent mechanisms in the control of NADPH oxidase–associated increased reactive oxygen species production in preeclampsia. These data show that preeclampsia is associated with a predisposition to increased agonist-stimulated NADPH oxidase–mediated reactive oxygen species production. The enhancement of reactive oxygen species generation may be important in mediating the endothelial dysfunction seen in preeclampsia.

Prognostic value of mid-regional pro-adrenomedullin levels taken on admission and discharge in non-ST-elevation myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) II study.

OBJECTIVES The purpose of this study was to assess the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non-ST-elevation myocardial infarction (MI) and identify values to aid clinical decision making. N-terminal pro-B-type natriuretic peptide and GRACE (Global Registry of Acute Coronary Events) score were used as comparators. BACKGROUND sAM is a stable precursor of adrenomedullin. METHODS We measured plasma sAM on admission and discharge in 745 non-ST-elevation MI patients (514 men, median age 70.0 +/- 12.7 years). The primary end point was a composite of death, heart failure, hospitalization, and recurrent acute MI over mean follow-up of 760 days (range 150 to 2,837 days), with each event assessed individually as secondary end points. RESULTS During follow-up, 120 (16.1%) patients died, and there were 65 (8.7%) hospitalizations for heart failure and 77 (10.3%) recurrent acute MIs. Both admission and discharge levels were increased (median 0.81 nmol/l [range 0.06 to 5.75 nmol/l] and 0.76 nmol/l [range 0.25 to 6.95 nmol/l], respectively) compared with established normal ranges. Multivariate adjusted Cox regression models revealed that both were associated with the primary end point (hazard ratio: 9.75 on admission and 7.54 on discharge; both p < 0.001). Admission sAM was particularly associated with early (<30 days) mortality (c-statistic = 0.90, p < 0.001), and when compared with N-terminal pro-B-type natriuretic peptide and GRACE score, it was the only independent predictor of this end point. Admission sAM >1.11 nmol/l identified those at highest risk of death (p < 0.001). Patients with above-median admission sAM may benefit from revascularization. CONCLUSIONS sAM level is prognostic for death or heart failure. Admission levels are a strong predictor of early mortality and, when >1.11 nmol/l, complements the GRACE score to improve risk stratification.

N-terminal pro B type natriuretic peptide complements the GRACE risk score in predicting early and late mortality following acute coronary syndrome

The GRACE (Global Registry of Acute Coronary Events) risk score has been shown to offer predictive power with regard to death and AMI (acute myocardial infarction) in patients with ACS (acute coronary syndromes). NT-proBNP (N-terminal pro-B-type natriuretic peptide) has also been found to be useful in predicting mortality following ACS. In the present study, we sought to investigate the use of the GRACE score and NT-proBNP levels at predicting risk of early and late deaths following ACS. We studied 1033 patients (740 men, mean age 66.5+/-12.7 years) with AMI. Blood was drawn once within 24 h following the onset of chest pain. The plasma concentration of NT-proBNP was determined using an in-house non-competitive immunoassay. Patients were GRACE risk scored. The 30-day mortality was 3.7% and the 6-month mortality was 7.8%, and all were related to higher GRACE risk scores (P=0.001 for trend). Higher NT-proBNP levels were also related to increased mortality (P<0.0001). In a Cox proportional hazards model, independent predictors of 30-day and 6-month mortality included NT-proBNP levels and the GRACE risk score. The receiver-operating curve for the GRACE risk score was complemented by NT-proBNP levels for prediction of 30-day mortality [AUC (area under the curve), 0.85] and 6-month mortality (AUC, 0.81). NT-proBNP gives complementary information to the GRACE risk score for predicting early and late mortality. The inclusion of the NT-proBNP blood test is useful in risk-stratifying patients after ACS.