Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.

BACKGROUND: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. METHODS: Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. RESULTS: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P=0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. CONCLUSIONS: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.

Copeptin for the prediction of recurrent cerebrovascular events after transient ischemic attack: results from the CoRisk study.

BACKGROUND AND PURPOSE: Copeptin has been associated with recurrent cerebrovascular events after transient ischemic attack (TIA). In an independent cohort, we evaluated copeptin for the prediction of recurrent cerebrovascular events within 3 months after TIA and assessed the incremental value of copeptin compared with the ABCD2 (age, blood, clinical features of TIA, duration of symptoms, presence of diabetes mellitus) and ABCD3-I (ABCD2, dual TIA [the presence of ≥2 TIA symptoms within 7 days], imaging [the presence of abnormal findings on neuroimaging]) scores. METHODS: This prospective, multicenter cohort study was conducted at 3 tertiary Stroke Centers in Switzerland and Germany. RESULTS: From March 2009 through April 2011, we included 302 patients with TIA admitted within 24 hours from symptom onset. Of 28 patients with a recurrent cerebrovascular event within 3 months (stroke or TIA), 11 patients had a stroke. Although the association of copeptin with recurrent cerebrovascular events was not significant, the association with stroke alone as end point was significant. After adjusting for the ABCD2 score, a 10-fold increase in copeptin levels was associated with an odds ratio for stroke of 3.39 (95% confidence interval, 1.28-8.96; P=0.01). After addition of copeptin to the ABCD2 score, the area under the curve of the ABCD2 score improved from 0.60 (95% confidence interval, 0.46-0.74) to 0.74 (95% confidence interval, 0.60-0.88, P=0.02). In patients with MRI (n=223), the area under the curve of the ABCD3-I score increased in similar magnitude, although not significantly. Based on copeptin, 31.2% of patients were correctly reclassified across the risk categories of the ABCD2 score (net reclassification improvement; P=0.17). CONCLUSIONS: Copeptin improved the prognostic value of the ABCD2 score for the prediction of stroke but not TIA, and it may help clinicians in refining risk stratification for patients with TIA. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00878813.

The prognostic value of midregional proatrial natriuretic peptide in patients with hemorrhagic stroke.

BACKGROUND: Atrial natriuretic peptide (ANP) is a well-known prognostic marker of outcome and mortality in patients with cardiovascular disease. Midregional proatrial natriuretic peptide (MR-proANP) is a stable fragment of the ANP precursor hormone. As a prognostic marker after ischemic stroke, it reliably predicts poststroke mortality and functional outcome. This study aimed to analyze the prognostic value of MR-proANP in patients with hemorrhagic stroke, i.e. subarachnoid (SAH) and intracerebral hemorrhage (ICH). METHODS: MR-proANP was analyzed in patients with spontaneous SAH or spontaneous ICH. All patients were prospectively randomized into two treatment arms: (1) a prophylactic normothermia group with a target core temperature 36.5°C using endovascular cooling, and (2) a control group with conventional stepwise predefined fever management using antipyretic medication and surface cooling. Blood samples were obtained on admission and on days 4 and 7. Measurement of MR-proANP was performed in serum using sandwich immunoassay. The primary endpoint was functional outcome [assessed by the Glasgow Outcome Score (GOS)] and the secondary endpoints were mortality within 180 days after hemorrhagic stroke and influence of temperature on MR-proANP. A favorable outcome was defined as GOS 4-5, and the patients were considered to have a poor outcome with a 180-day GOS score between 1 and 3. RESULTS: Analysis of MR-proANP was performed in 24 patients with spontaneous SAH and 22 patients with spontaneous ICH. MR-proANP was elevated on days 4 and 7 as compared to baseline levels (p < 0.05 and p < 0.001, respectively). High MR-proANP levels (>120 pmol/l) were associated with increased mortality and poor outcome (after 180 days; p < 0.05, respectively). There was no significant difference regarding MR-proANP serum concentrations between the endovascular and the control groups. CONCLUSIONS: Increased levels of MR-proANP are independently associated with poor functional outcome and increased mortality after 180 days in patients with hemorrhagic stroke. Endovascular temperature control had no significant influence on MR-proANP levels.

The role of copeptin as a diagnostic and prognostic biomarker for risk stratification in the emergency department.

The hypothalamic-pituitary-adrenal axis is activated in response to stress. One of the activated hypothalamic hormones is arginine vasopressin, a hormone involved in hemodynamics and osmoregulation. Copeptin, the C-terminal part of the arginine vasopressin precursor peptide, is a sensitive and stable surrogate marker for arginine vasopressin release. Measurement of copeptin levels has been shown to be useful in a variety of clinical scenarios, particularly as a prognostic marker in patients with acute diseases such as lower respiratory tract infection, heart disease and stroke. The measurement of copeptin levels may provide crucial information for risk stratification in a variety of clinical situations. As such, the emergency department appears to be the ideal setting for its potential use. This review summarizes the recent progress towards determining the prognostic and diagnostic value of copeptin in the emergency department.

Midregional proadrenomedullin for prediction of cardiovascular events in coronary artery disease: results from the AtheroGene study.

BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a newly identified prognostic marker in heart failure. We evaluated the prognostic impact of MR-proADM in a cohort of patients with symptomatic coronary artery disease according to their clinical presentation. METHODS: We measured baseline MR-proADM concentrations in 2240 individuals from the prospective AtheroGene study and evaluated the prognostic impact on future fatal and nonfatal cardiovascular events during a follow-up period of 3.6 (1.6) years. RESULTS: The sample comprised 1355 individuals with stable angina pectoris (SAP) and 885 with acute coronary syndrome (ACS). A cardiovascular event occurred in 192 people. Individuals presenting with SAP had only slightly lower plasma MR-proADM concentrations than those with ACS (0.53 vs 0.55 nmol/L, P=0.006). MR-proADM showed a moderate association with age, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), glomerular filtration rate, serum C-reactive protein, hypertension, diabetes, and prevalent multivessel disease (all P<0.0005). Individuals suffering from a cardiovascular event had higher MR-proADM concentrations at baseline in both groups (SAP 0.63 vs 0.53 nmol/L and ACS 0.65 nmol/L vs 0.55 nmol/L, both P<0.0005). Cox regression analysis incorporating various variables of cardiovascular risk and NT-proBNP revealed a hazard ratio of 1.4 (95% CI 1.2-1.6; P<0.0005) per increment of MR-proADM by 1SD. In risk models for secondary prevention, MR-proADM provided information comparable to that of NT-proBNP. CONCLUSIONS: MR-proADM is an independent predictor for future cardiovascular events in patients with symptomatic coronary artery disease, providing information comparable to NT-proBNP for secondary risk stratification.

Plasma pro-endothelin-1 and respiratory distress in newborn infants.

Plasma concentrations of the stable endothelin-1 precursor, C-terminal portion of the endothelin-1 precursor, determined prospectively in 293 newborn infants (gestational age, 24-41 weeks) at birth and on day 3 of life were unrelated to gestational age at birth, but strongly associated with respiratory distress when measured on day 3 of life.

Copeptin: a marker for stress reaction in fetuses with intrauterine growth restriction.

OBJECTIVE: To compare venous cord plasma concentrations of 4 vasoactive peptide precursors: carboxy-terminal proarginine vasopressin, CT-prondothelin (ET)-1, midregional proadrenomedullin, and MR-proatrial natriuretic peptide, between fetuses with intrauterine growth restriction and appropriate for gestational age controls. STUDY DESIGN: Matched-pair analysis of 12 fetuses with significant intrauterine growth restriction and 42 healthy appropriate for gestational age control fetuses. All infants were singletons, delivered by elective section after 34 weeks and without chromosomal abnormalities. RESULTS: Umbilical cord plasma copeptin levels (median [range]) were 4-fold higher in intrauterine growth restriction infants than in matched appropriate for gestational age controls: 23.2 (6.7-449) vs 5.1 (2.5-53) pmol/L (P < .001). Multivariate regression analysis revealed an association between copeptin and umbilical artery resistance index z-score (P = .034). The 3 other precursor peptides showed no changes. CONCLUSION: High copeptin concentrations in the cord blood of intrauterine growth restriction newborns reflect a fetal stress response and support the fetal programming hypothesis.

Plasma midregional proadrenomedullin in newborn infants: impact of prematurity and perinatal infection.

INTRODUCTION: Adrenomedullin (ADM) is one of the strongest endogenous vasodilating hormones. Its stable by-product midregional-proADM (MR-proADM) is an established indicator of systemic infection and cardiovascular compromise in adult patients. METHODS: A prospective cross-sectional study was performed to investigate the perinatal factors affecting MR-proADM plasma concentrations in 328 newborn infants with a gestational age (GA) between 24 and 41 wk. RESULTS: Blood samples were obtained in 270 infants from umbilical veins (with additional 108 paired samples from umbilical arteries), and at 2-3 d of life in 183 infants. Paired venous and arterial umbilical cord MR-proADM concentrations were closely related (Spearman's rank order correlation coefficient (R(s)) = 0.825, P < 0.001). MR-proADM concentrations at birth and at 2-3 d were inversely related to GA (R(s) = -0.403 and R(s) = -0.541, respectively) and birth weight (BW; R(s) = -0.421 and R(s) = -0.530, respectively; all P < 0.001). On stepwise regression analysis, clinical chorioamnionitis and umbilical arterial blood base excess retained a significant impact on MR-proADM cord venous blood concentrations. At 2-3 d of life, histologic chorioamnionitis and GA at delivery were significantly associated with MR-proADM levels. DISCUSSION: As compared with adults, MR-proADM concentrations are elevated in neonates, especially those born very preterm. Immaturity and infection, which both feature low systemic vascular resistance, are related to increased MR-proADM concentrations.

The effect of diabetes on the diagnostic and prognostic performance of mid-region pro-atrial natriuretic peptide and mid-region pro-adrenomedullin in patients with acute dyspnea.

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

The atrial natriuretic peptide does not serve osmoregulation but predicts outcome following brain injury.

Atrial natriuretic peptide (ANP) plays an important role in body fluid homeostasis. ANP has been established as a marker of cardiac dysfunction and may play a role in brain edema development after traumatic brain injury (TBI). In order to identify its specific assignment following TBI, we related clinical data and treatment variables in 63 patients to longitudinal midregional (MR) proatrail natriuretic peptide (ANP) measurements. ANP correlated significantly to age (p < 0.0001) and vasopressin release (p < 0.001). Following TBI, ANP was increased initially and on day 3 (cut-off 100 pg/L) in 22% of the patients, in 31% on day 7, and was normalized at follow-up examination. The group comparison revealed that ANP levels did not significantly differ with regard to injury severity, but that high ANP levels predicted a worse Glasgow Outcome Score at 6 months (p < 0.05). While the initially intact osmoregulation - a correlation of urine volume and high serum sodium (r = 0.536, p = 0.003) or low urine osmolality (r = -0.556, p = 0.009) - got lost post-injury, the ANP release was triggered by volume load (p < 0.005). High ANP levels correlated with the neuroendocrine stress response, i.e., high cortisol (p = 0.05) and prolactin (p < 0.001) levels. We conclude that MR-proANP measurements reveal a significant predictive function for the prognosis of TBI.

The course of adrenomedullin and endothelin levels in patients with vasodilatory shock after cardiac surgery compared to patients after uncomplicated elective cardiac surgery.

PURPOSE: The aim of this study was to analyse the course of adrenomedullin (ADM) and endothelin-1 (ET-1) levels in patients with vasodilatory shock after cardiac surgery and to explore differences compared to patients after uncomplicated coronary artery bypass graft (CABG) surgery. ADM and ET-1 are involved in the vasomotor response during vasodilatory shock. MATERIALS AND METHODS: We included 32 patients with vasodilatory shock (study group) and 10 patients after uncomplicated CABG surgery (control group). Daily measurements of MR-proADM and CT-proET-1 (stable surrogate markers for ADM and ET-1) were collected during the first 7 postoperative days. RESULTS: MR-proADM and CT-proET-1 levels were significantly elevated in the study group when compared to the control group. In addition, the course of both biomarkers was significantly different in the study versus control group. Higher levels of both biomarkers were associated with organ dysfunction (higher maximum multiple organ dysfunction score, acute kidney injury). CONCLUSIONS: Significantly higher levels of MR-proADM and CT-proET-1 and a different course of both biomarkers were observed in patients with vasodilatory shock after cardiac surgery and seemed to be associated with organ dysfunction.

Circulating multimeric immune complexes contribute to immunopathology in COVID-19.

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document excessive FcγRIIIA/CD16A activation in patients developing severe or critical COVID-19 but not in those with mild disease. We identify two independent ligands mediating extreme FcγRIIIA/CD16A activation. Soluble circulating IgG immune complexes (sICs) are detected in about 80% of patients with severe and critical COVID-19 at levels comparable to active systemic lupus erythematosus (SLE) disease. FcγRIIIA/CD16A activation is further enhanced by afucosylation of SARS-CoV-2 specific IgG. Utilizing cell-based reporter systems we provide evidence that sICs can be formed prior to a specific humoral response against SARS-CoV-2. Our data suggest a cycle of immunopathology driven by an early formation of sICs in predisposed patients. These findings suggest a reason for the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19. The involvement of circulating sICs in the promotion of immunopathology in predisposed patients opens new possibilities for intervention strategies to mitigate critical COVID-19 progression.

Prognosis is worse with elevated cardiac troponin in nonacute coronary syndrome compared with acute coronary syndrome.

BACKGROUND: Cardiac troponin (cTn) can be elevated in many patients presenting to the emergency department (ED) with chest pain but without a diagnosis of acute coronary syndrome (ACS). We compared the prognostic significance of cTn in these different populations. METHODS: We retrospectively analyzed the CHOPIN study, which enrolled patients who presented to the ED with chest pain. Patients were grouped as ACS, non-ACS cardiovascular disease, noncardiac chest pain and chest pain not otherwise specified (NOS). We examined the prognostic ability of cTnI for the clinical endpoints of mortality and major adverse cardiovascular event (MACE; a composite of acute myocardial infarction, unstable angina, revascularization, reinfarction, and congestive heart failure and stroke) at 180-day follow-up. RESULTS: Among 1982 patients analyzed, 14% had ACS, 21% had non-ACS cardiovascular disease, 31% had a noncardiac diagnosis and 34% had chest pain NOS. cTnI elevation above the 99th percentile was observed in 52, 18, 6 and 7% in these groups, respectively. cTnI elevation was associated with mortality and MACE, and their relationships were more prominent in noncardiac diagnosis and chest pain NOS than in ACS and non-ACS cardiovascular diagnoses for mortality, and in non-ACS patients than in ACS patients for MACE (hazard ratio for doubling of cTnI 1.85, 2.05, 8.26 and 4.14, respectively; P for interaction 0.011 for mortality; 1.04, 1.23, 1.54 and 1.42, respectively; P for interaction <0.001 for MACE). CONCLUSION: In patients presenting to the ED with chest pain, cTnI elevation was associated with a worse prognosis in non-ACS patients than in ACS patients.

Plasma copeptin and the risk of diabetes mellitus.

BACKGROUND: Animal studies suggest that the arginine vasopressin system may play a role in glucose metabolism, but data from humans are limited. METHODS AND RESULTS: We analyzed plasma copeptin (copeptin), a stable C-terminal fragment of the arginine vasopressin prohormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742; mean age, 58 years; 60% women) and multivariable logistic regression, we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes mellitus at baseline, insulin resistance (top quartile of fasting plasma insulin among nondiabetic subjects), and incident diabetes mellitus on long-term follow-up. New-onset diabetes mellitus was ascertained through 3 national and regional registers. All models were adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein. In cross-sectional analyses, increasing copeptin was associated with prevalent diabetes mellitus (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow-up, 174 subjects (4%) developed new-onset diabetes mellitus. The odds of developing diabetes mellitus increased across increasing quartiles of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios, 1.0, 1.37, 1.79, and 2.09; P for trend=0.004). The association with incident diabetes mellitus remained significant in analyses restricted to subjects with fasting whole blood glucose <5.4 mmol/L at baseline (adjusted odds ratios, 1.0, 1.80, 1.92, and 3.48; P=0.001). CONCLUSIONS: Elevated copeptin predicts increased risk for diabetes mellitus independently of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel antidiabetic treatments, and metabolic side effects from arginine vasopressin system modulation.

Post cardiac surgery vasoplegia is associated with high preoperative copeptin plasma concentration.

INTRODUCTION: Post cardiac surgery vasodilatation (PCSV) is possibly related to a vasopressin deficiency that could relate to chronic stimulation of adeno-hypophysis. To assess vasopressin system activation, a perioperative course of copeptin and vasopressin plasma concentrations were studied in consecutive patients operated on for cardiac surgery. METHODS: Sixty-four consecutive patients scheduled for elective cardiac surgery with cardiopulmonary bypass were studied. Hemodynamic, laboratory and clinical data were recorded before and during cardiopulmonary bypass, and at the eighth postoperative hour (H8). At the same time, blood was withdrawn to determine plasma concentrations of arginine vasopressin (AVP, radioimmunoassay) and copeptin (immunoluminometric assay). PCSV was defined as mean arterial blood pressure < 60 mmHg with cardiac index ≥ 2.2 l/min/m², and was treated with norepinephrine to restore mean blood pressure > 60 mmHg. Patients with PCSV were compared with the other patients (controls). Student's t test, Fisher's exact test, or nonparametric tests (Mann-Whitney, Wilcoxon) were used when appropriate. Correlation between AVP and copeptin was evaluated and receiver-operator characteristic analysis assessed the utility of preoperative copeptin to distinguish between controls and PCSV patients. RESULTS: Patients who experienced PCSV had significantly higher copeptin plasma concentration before cardiopulmonary bypass (P < 0.001) but lower AVP concentrations at H8 (P < 0.01) than controls. PCSV patients had preoperative hyponatremia and decreased left ventricle ejection fraction, and experienced more complex surgery (redo). The area under the receiver-operator characteristic curve of preoperative copeptin concentration was 0.86 ± 0.04 (95% confidence interval = 0.78 to 0.94; P < 0.001). The best predictive value for preoperative copeptin plasma concentration was 9.43 pmol/l with a sensitivity of 90% and a specificity of 77%. CONCLUSIONS: High preoperative copeptin plasma concentration is predictive of PSCV and suggests an activation of the AVP system before surgery that may facilitate depletion of endogenous AVP stores and a relative AVP deficit after surgery.

Changes in copeptin and bioactive vasopressin in runners with and without hyponatremia.

OBJECTIVE: To evaluate changes in both the N-terminal (arginine vasopressin; AVP) and C-terminal (copeptin) fragments of the vasopressin prohormone before, during, and after an ultramarathon race and to assess vasopressin and copeptin concentrations in runners with and without hyponatremia. DESIGN: Observational study. SETTING: Three trials (2 sodium balance and 1 hyponatremia treatment) in 2 separate approximately 160-km footraces [Western States Endurance Run (WSER) and Javelina Jundred (JJ100)]. PARTICIPANTS: Six hyponatremic and 20 normonatremic runners; 19 finishers with 7 completing 100 km. MAIN OUTCOME MEASURES: Plasma AVP ([AVP]p), copeptin ([copeptin]p), sodium ([Na]p), and protein (%plasma volume change; %PV) concentrations. RESULTS: In the WSER Sodium Trial, a 3-fold prerace to postrace increase in both [AVP]p (0.7 ± 0.4 to 2.7 ± 1.9 pg/mL; P < 0.05) and [copeptin]p (10.3 ± 12.5 to 28.2 ± 16.3 pmol/L; nonsignificant) occurred, despite a 2 mEq/L decrease in [Na]p (138.7 ± 2.3 to 136.7 ± 1.6 mEq/L; NS). A significant correlation was noted between [AVP]p and [copeptin]p postrace (r = 0.82; P < 0.05). In the WSER Treatment Trial, despite the presence of hyponatremia pretreatment versus posttreatment ([Na]p = 130.3 vs 133.5 mEq/L, respectively), both [AVP]p (3.2 vs 2.1 pg/mL) and [copeptin]p (22.5 vs 24.9 pmol/L) were well above the detectable levels. A significant correlation was noted between [AVP]p and [copeptin]p 60 minutes after treatment (r = 0.94; P < 0.05). In the JJ100 Sodium Trial, significant correlations were found between [copeptin]p change and %PV change (r = -0.34; P < 0.05) and between [AVP]p change and [Na]p change (r = 0.39; P < 0.05) but not vice-versa. CONCLUSIONS: [Copeptin]p seems to be a reliable surrogate of stimulated [AVP]p during exercise. Nonosmotic vasopressin stimulation occurs during ultradistance running. [Copeptin]p may better reflect chronic (%PV) vasopressin secretion under conditions of endurance exercise.

Prognostic value of copeptin: one-year outcome in patients with acute stroke.

BACKGROUND AND PURPOSE: An accurate long-term outcome prediction may improve management of stroke patients. We investigated the ability of copeptin to predict 1-year outcome in stroke patients. METHODS: In this preplanned post hoc analysis, the National Institutes of Health Stroke Scale score and copeptin levels were measured on admission in a cohort of patients with ischemic stroke. The primary end point was functional outcome (modified Rankin Scale score <3 or 3-6) after 1 year. The secondary end point was all-cause mortality. RESULTS: Of 362 patients, 341 (94.2%) completed the 1-year follow-up, 146 (43%) patients had an unfavorable functional outcome, and 66 (20%) died. Multivariate logistic-regression analysis adjusted for age and National Institutes of Health Stroke Scale score showed that copeptin was an independent predictor of functional outcome (odds ratio=4.00; 95% CI, 1.94-8.19) and death (odds ratio=2.68; 95% CI, 1.24-5.82). The area under the receiver operating characteristic curve of copeptin was 0.72 (95% CI, 0.67-0.77) for functional outcome and 0.74 (95% CI, 0.69-0.78) for mortality. Copeptin improved the area under the receiver operating characteristic curve of the National Institutes of Health Stroke Scale score for functional outcome from 0.70 (95% CI, 0.64-0.74) to 0.76 (95% CI, 0.71-0.82; P=0.002) and for mortality from 0.74 (95% CI, 0.69-0.78) to 0.78 (95% CI, 0.71-0.85; P=0.04). CONCLUSIONS: Copeptin levels are a useful, complementary tool to predict functional outcome and mortality 1 year after stroke. CLINICAL TRIAL REGISTRATION: ISCTRN 00390962; clinicaltrials.gov No. NCT00390962.

Copeptin: a novel, independent prognostic marker in patients with ischemic stroke.

OBJECTIVE: Early prediction of outcome in patients with ischemic stroke is important. Vasopressin is a stress hormone. Its production rate is mirrored in circulating levels of copeptin, a fragment of provasopressin. We evaluated the prognostic value of copeptin in acute stroke patients. METHODS: In a prospective observational study, copeptin was measured using a new sandwich immunoassay on admission in plasma of 362 consecutive patients with an acute ischemic stroke. The prognostic value of copeptin to predict the functional outcome (defined as a modified Rankin Scale score of or=3), mortality within 90 days, was compared with the National Institutes of Health Stroke Scale score and with other known outcome predictors. RESULTS: Patients with an unfavorable outcomes and nonsurvivors had significantly increased copeptin levels on admission (p <0.0001 and p <0.0001). Receiver operating characteristics to predict functional outcome and mortality demonstrated areas under the curve of copeptin of 0.73 (95% confidence interval [CI], 0.67-0.78) and 0.82 (95% CI, 0.76-0.89), which was comparable with the National Institutes of Health Stroke Scale score but superior to C-reactive protein and glucose (p <0.01). In multivariate logistic regression analysis, copeptin was an independent predictor of functional outcome and mortality, and improved the prognostic accuracy of the National Institutes of Health Stroke Scale to predict functional outcome (combined areas under the curve, 0.79; 95% CI, 0.74-0.84; p <0.01) and mortality (combined areas under the curve, 0.89; 95% CI, 0.84-0.94; p <0.01). INTERPRETATION: Copeptin is a novel, independent prognostic marker improving currently used risk stratification of stroke patients. Ann Neurol 2009;66:799-808.

Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) accounts for a high mortality and morbidity. Early prediction of outcome is crucial for optimized care and treatment decision. Copeptin, the C-terminal part of provasopressin, has emerged as a new prognostic marker in a variety of diseases, but its prognostic value in ICH is unknown. METHODS: In 40 consecutive patients who were admitted to the hospital within 72 hours after a spontaneous ICH, the plasma copeptin level was measured with a sandwich immunoassay upon admission. The prognostic value of copeptin to predict 30 day mortality and functional outcome after 90 days was assessed. A favorable outcome was defined as a Barthel score above 85 and a score below 3 on the Modified Rankin Scale. RESULTS: Copeptin correlated positively with hematoma volume (r = 0.32, p < 0.05) and negatively with the Glasgow Coma Scale (GCS) on admission (r = -0.35, p < 0.05). Copeptin levels were higher in patients who died within 30 days than in 30-day survivors (179.0 pmol/l (IQR 33.7- 566.0) vs. 12.9 pmol/l (IQR 5.2 - 42.8), p = 0.003). Copeptin levels were also higher in patients with an unfavorable functional outcome at 90 days compared to patients with a favorable outcome (32.4 pmol/l (IQR 9.5-97.8) vs. 11.9 pmol/l (IQR 3.2-19.8), p = 0.04). For the prediction of death, receiver-operating-characteristics analysis revealed an area under the curve (AUC) for copeptin of 0.88 (95%CI 0.75-1.00). The predictive value of the copeptin concentration was thus similar to that of GCS (AUC 0.82 (95%CI 0.59-1.00) p = 0.53), of the ICH Score (AUC 0.89, (95%CI 0.76-1.00), p = 0.94) and the ICH Grading Scale (AUC 0.86 (95%CI 0.69-1.00), p = 0.81). CONCLUSIONS: Copeptin is a new prognostic marker in patients with an ICH. If this finding can be confirmed in larger studies, copeptin might be an additional valuable tool for risk stratification and decision-making in the acute phase of ICH.

Copeptin and risk stratification in patients with acute dyspnea.

INTRODUCTION: The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of Copeptin, the C-terminal part of the vasopressin prohormone alone and combined to N-terminal pro B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea. METHODS: We conducted a prospective, observational cohort study in the emergency department of a university hospital and enrolled 287 patients with acute dyspnea. RESULTS: Copeptin levels were elevated in non-survivors (n = 29) compared to survivors at 30 days (108 pmol/l, interquartile range (IQR) 37 to 197 pmol/l) vs. 18 pmol/l, IQR 7 to 43 pmol/l; P < 0.0001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.83 (95% confidence interval (CI) 0.76 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for Copeptin, NT-proBNP and BNP, respectively (Copeptin vs. NTproBNP P = 0.21; Copeptin vs. BNP P = 0.002). When adjusted for common cardiovascular risk factors and NT-proBNP, Copeptin was the strongest independent predictor for short-term mortality in all patients (HR 3.88 (1.94 to 7.77); P < 0.001) and especially in patients with acute decompensated heart failure (ADHF) (HR 5.99 (2.55 to 14.07); P < 0.0001). With the inclusion of Copeptin to the adjusted model including NTproBNP, the net reclassification improvement (NRI) was 0.37 (P < 0.001). An additional 30% of those who experienced events were reclassified as high risk, and an additional 26% without events were reclassified as low risk. CONCLUSIONS: Copeptin is a new promising prognostic marker for short-term mortality independently and additive to natriuretic peptide levels in patients with acute dyspnea.