Lipoprotein(a) as a blood marker for large artery atherosclerosis stroke etiology: validation in a prospective cohort from a swiss stroke center.

BACKGROUND: Lipoprotein (a) [Lp(a)] serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort. METHODS: This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients [NCT00878813]), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers. RESULTS: Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10and#xA0;Lp(a) with LAA stroke aetiology (aOR 1.47 [95% CI 1.03and#x2013;2.09], p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes. CONCLUSIONS: In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov. REGISTRATION NUMBER: NCT00878813.

Discordance between LDL-C and apolipoprotein B is associated with large-artery-atherosclerosis ischemic stroke in patients ⩽70 years of age.

BACKGROUND AND AIMS: Low density lipoprotein (LDL-C) and other atherogenic lipoproteins are coated by apolipoprotein B100 (apoB). The correlation between LDL-C and apoB is usually thight, but in some cases LDL-C underestimates apoB levels and residual cardiovascular risk. We aimed to assess if a discordance of LDL-C-levels with apoB levels is associated with LAA stroke. METHODS: We included patients with an acute ischemic stroke from two prospective studies enrolled at the University Hospital Bern, Basel and Zurich, Switzerland. LDL-C and apoB were measured within 24 h of symptom onset. By linear regression, for each LDL-C, we computed the expected apoB level assuming a perfect correlation. Higher-than-expected apoB was defined as apoB level being in the upper residual tertile. RESULTS: Overall, we included 1783 patients, of which 260 had a LAA stroke (15%). In the overall cohort, higher-than-expected apoB values were not associated with LAA. However, a significant interaction with age was present. Among the 738 patients ⩽70 years of age, a higher-than-expected apoB was more frequent in patients with LAA- versus non LAA-stroke (48% vs 36%, p = 0.02). In multivariate analysis, a higher-than-expected apoB was associated with LAA stroke (aOR = aOR 2.48, 95%CI 1.14-5.38). Among those aged ⩽70 years and with LAA, 11.7% had higher than guideline-recommended apoB despite LDL-C ⩽ 1.8 mmol/L (<70 mg/dl), compared to 5.9% among patients with other stroke etiologies (p = 0.04). A triglyceride cut-off of ⩾0.95 mmol/L had, in external validation, a sensitivity of 71% and specificity of 52% for apoB ⩾ 0.65 g/L among patients with LDL-C <1.8 mmol/L. CONCLUSIONS: Among patients aged ⩽70 years, a higher-than-expected apoB was independently associated with LAA stroke. Measuring apoB may help identify younger stroke patients potentially benefiting from intensified lipid-lowering therapy.

The Role of Electrocardiographic Markers for Predicting Atrial Fibrillation in Patients with Acute Ischemic Stroke: Data from the BIOSIGNAL Cohort Study.

BACKGROUND AND AIMS: P-wave abnormalities in the 12-lead electrocardiogram (ECG) have been associated with a higher risk of acute ischemic stroke (AIS) as well as atrial fibrillation (AF). This study aimed to assess pre-determined ECG criteria during sinus rhythm in unselected AIS patients and their value for predicting newly diagnosed atrial fibrillation (NDAF) after hospital admission. METHODS: P-wave alterations were measured on 12-lead ECG on admission in all consecutively enrolled patients without known AF between October 2014 and 2017. The outcome of interest was NDAF, identified by prolonged electrocardiographic monitoring within one year after the index AIS. Univariable and multivariable logistic regression was applied to assess the magnitude and independence of the association between pre-selected ECG markers and NDAF. The discriminatory accuracy was evaluated with the area under the receiver operating characteristic curve (AUC), and the incremental prognostic value was estimated with the net reclassification index. RESULTS: NDAF was detected in 87 (10%) of 856 patients during a follow-up of 365 days. Out of the pre-selected ECG parameters, advanced interatrial block (aIAB) and PR interval in lead II were independently associated with NDAF in univariable regression analysis. Only aIAB remained a significant predictor in multivariable analysis. Adding aIAB to the best-performing multivariable regression model improved the discriminatory accuracy to predict NDAF from an AUC of 0.78 (95%-CI 0.77-0.80) to 0.81 (95%-CI 0.80-0.83, p < 0.001). CONCLUSION: aIAB is independently and highly associated with NDAF in patients with AIS, has high inter-rater reliability, and therefore may be helpful to refine diagnostic work-up to search for AF in AIS.

High posterior cerebral artery flow predicts ischemia recurrence in patients with internal carotid artery occlusion.

Recurrent stroke is a dreaded complication of symptomatic internal carotid artery occlusion (ICAO). Transcranial Duplex (TCD)-derived increased flow velocity in the ipsilateral posterior cerebral artery (PCA)-P2 segment indicates activated leptomeningeal collateral recruitment and hemodynamic impairment. Leptomeningeal collaterals are pial vascular connections between the anterior and posterior vascular territories. These secondary collateral routes are activated when primary collaterals via the Circle of Willis are insufficient. Our goal was to test the TCD parameter PCA-P2 flow for prediction of ipsilateral ischemia recurrence. We retrospectively analyzed clinical and ultrasound parameters in patients with ICAO. Together with clinical variables, we tested systolic PCA-P2 flow velocity as predictor of a recurrent ischemic event using logistic regression models. Of 111 patients, 13 showed a recurrent ischemic event within the same vascular territory. Increased flow in the ipsilateral PCA-P2 on transcranial ultrasound (median and interquartile range [IQR]: 60 cm/s [IQR 26] vs. 86 cm/s [IQR 41], p = <0.001), as well as previous transient ischemic attack (TIA) and low NIHSS were associated with ischemia recurrence. Combined into one model, accuracy of these parameters to predict recurrent ischemia was 89.2%. Our data suggest that in patients with symptomatic ICAO, flow increases in the ipsilateral PCA-P2 suggest intensified compensatory efforts when other collaterals are insufficient. Together with the clinical variables, this non-invasive and easily assessable duplex parameter detects ICAO patients at particular risk of recurrent ischemia.

Serum S-100B adds incremental value for the prediction of symptomatic intracranial hemorrhage and brain edema after acute ischemic stroke.

Background: Early identification of patients developing symptomatic intracranial hemorrhage and symptomatic brain edema after acute ischemic stroke is essential for clinical decision-making. Astroglial protein S-100B is a marker of blood-brain barrier disruption, which plays an important role in the formation of intracranial hemorrhage and brain edema. In this study, we assessed the prognostic value of serum S-100B for the development of these complications. Methods: Serum S-100B levels were measured within 24 h from symptom onset in 1749 consecutive acute ischemic stroke patients from the prospective, observational, multicenter BIOSIGNAL cohort study (mean age 72.0 years, 58.3% male). To determine symptomatic intracranial hemorrhage or symptomatic brain edema, follow-up neuroimaging was performed in all patients receiving reperfusion therapy or experiencing clinical worsening with an NIHSS increase of ⩾4. Results: Forty six patients (2.6%) developed symptomatic intracranial hemorrhage and 90 patients (5.2%) developed symptomatic brain edema. After adjustment for established risk factors, log10S-100B levels remained independently associated with both symptomatic intracranial hemorrhage (OR 3.41, 95% CI 1.7-6.9, p = 0.001) and symptomatic brain edema (OR 4.08, 95% CI 2.3-7.1, p < 0.001) in multivariable logistic regression models. Adding S-100B to the clinical prediction model increased the AUC from 0.72 to 0.75 (p = 0.001) for symptomatic intracranial hemorrhage and from 0.78 to 0.81 (p < 0.0001) for symptomatic brain edema. Conclusions: Serum S-100B levels measured within 24 h after symptom onset are independently associated with the development of symptomatic intracranial hemorrhage and symptomatic brain edema in acute ischemic stroke patients. Thus, S-100B may be useful for early risk-stratification regarding stroke complications.

Stroke-associated infections in patients with and without cancer.

Background: Cancer in stroke patients is associated with higher levels of inflammatory biomarkers and unfavorable poststroke outcomes. We thus explored whether there is a link between cancer and stroke-associated infections. Methods: Medical records of patients with ischemic stroke in 2014-2016 registered in the Swiss Stroke Registry of Zurich were retrospectively analyzed. Incidence, characteristics, treatment, and outcome of stroke-associated infections diagnosed within 7 days after stroke onset were tested for an association with cancer. Results: Among 1181 patients with ischemic stroke, 102 patients with cancer were identified. Stroke-associated infections occurred in 179 and 19 patients (17% and 19%) without and with cancer (P = .60), respectively, among them pneumonia in 95 and 10 patients (9% and 10%) and urinary tract infections in 68 and 9 patients (6% and 9%) (P = .74 and P = .32). Use of antibiotics was similar between groups. Levels of C-reactive protein (CRP) (P < .001), erythrocyte sedimentation rate (ESR) (P = .014) and procalcitonin (P = .015) were higher and levels of albumin (P = .042) and protein (P = .031) were lower in patients with cancer than without cancer. Among patients without cancer, higher CRP (P < .001), ESR (P < .001) and procalcitonin (P = .04) and lower albumin (P < .001) were associated with stroke-associated infections. Among cancer patients with or without infections, no significant differences in these parameters were observed. In-hospital mortality was associated with cancer (P < .001) and with stroke-associated infections (P < .001). However, among patients with stroke-associated infections, cancer was not associated with in-hospital mortality (P = .24) or 30-day mortality (P = .66). Conclusions: Cancer does not represent a risk factor for stroke-associated infections in this patient cohort.

Serum circulating sirtuin 6 as a novel predictor of mortality after acute ischemic stroke.

In a murine model of acute ischemic stroke, SIRT6 knockdown resulted in larger cerebral infarct size, worse neurological outcome, and higher mortality, indicating a possible neuro-protective role of SIRT6. In this study, we aimed at evaluating the prognostic value of serum SIRT6 levels in patients with acute ischemic stroke (AIS). Serum levels of SIRT6, collected within 72 h from symptom-onset, were measured in 317 consecutively enrolled AIS patients from the COSMOS cohort. The primary endpoint of this analysis was 90-day mortality. The independent prognostic value of SIRT6 was assessed with multivariate logistic and Cox proportional regression models. 35 patients (11%) deceased within 90-day follow-up. After adjustment for established risk factors (age, NIHSS, heart failure, atrial fibrillation, and C reactive protein), SIRT6 levels were negatively associated with mortality. The optimal cut-off for survival was 634 pg/mL. Patients with SIRT6 levels below this threshold had a higher risk of death in multivariable Cox regression. In this pilot study, SIRT6 levels were significantly associated with 90-day mortality after AIS; these results build on previous molecular and causal observations made in animal models. Should this association be confirmed, SIRT6 could be a potential prognostic predictor and therapeutic target in AIS.

A novel biomarker panel index improves risk stratification after ischemic stroke.

Background: We investigated 92 blood biomarkers implicated in the pathophysiological pathways of ischemic injury, inflammation, hemostasis, and regulation of vascular resistance to predict post-stroke mortality. Aim: Based on the most promising markers, we aimed to create a novel Biomarker Panel Index (BPI) for risk stratification. Methods: In this prospective study, we measured 92 biomarkers in 320 stroke patients. The primary outcome measure was mortality within 90 days. We estimated the association of each biomarker using logistic regression adjusting for multiple testing. The most significant 16 biomarkers were used to create the BPI. We fitted regression models to estimate the association and the discriminatory accuracy of the BPI with mortality and stroke etiology. Results: Adjusted for demographic and vascular covariates, the BPI remained independently associated with mortality (odds ratio (OR) 1.68, 95% confidence interval (CI): 1.29-2.18) and cardioembolic stroke etiology (OR 1.38, 95% CI: 1.10-1.74), and improved the discriminatory accuracy to predict mortality (area under the receiver operating characteristic curve (AUC) 0.93, 95% CI: 0.89-0.96) and cardioembolic stroke etiology (AUC 0.70, 95% CI: 0.64-0.77) as compared to the best clinical prediction models alone (AUC 0.89, 95% CI: 0.84-0.94 and AUC 0.66, 95% CI: 0.60-0.73, respectively). Conclusions: We identified a novel BPI improving risk stratification for mortality after ischemic stroke beyond established demographic and vascular risk factors. Furthermore, the BPI is associated with underlying cardioembolic stroke etiology. These results need external validation.

Measurement of Midregional Pro-Atrial Natriuretic Peptide to Discover Atrial Fibrillation in Patients With Ischemic Stroke.

BACKGROUND: Midregional pro-atrial natriuretic peptide (MR-proANP) is a promising biomarker to differentiate the underlying etiology of acute ischemic stroke (AIS). OBJECTIVES: This study aimed to determine the role of MR-proANP for classification as cardioembolic (CE) stroke, identification of newly diagnosed atrial fibrillation (NDAF), and risk assessment for major adverse cardiovascular events (MACE). METHODS: This study measured MR-proANP prospectively collected within 24 hours after symptom-onset in patients with AIS from the multicenter BIOSIGNAL (Biomarker Signature of Stroke Aetiology) cohort study. Primary outcomes were CE stroke etiology and NDAF after prolonged cardiac monitoring, as well as a composite outcome of MACE (recurrent cerebrovascular events, myocardial infarction, or cardiovascular death) within 1 year. Logistic/Poisson and subproportional hazard regression were applied to evaluate the association between MR-proANP levels and outcomes. Additionally, a model for prediction of NDAF was derived and validated as a decision tool for immediate clinical application. RESULTS: Between October 1, 2014, and October 31, 2017, this study recruited 1,759 patients. Log10MR-proANP levels were associated with CE stroke (OR: 7.96; 95% CI: 4.82-13.14; risk ratio: 3.12; 95% CI: 2.23-4.37), as well as NDAF (OR: 35.3; 95% CI: 17.58-71.03; risk ratio: 11.47; 95% CI: 6.74-19.53), and MACE (subdistributional HR: 2.02; 95% CI: 1.32-3.08) during follow-up. The model to predict NDAF including only age and MR-proANP levels had a good discriminatory capacity with an area under the curve of 0.81 (95% CI: 0.76-0.86), was well calibrated (calibration in the large: -0.086; calibration slope 1.053), and yielded higher net-benefit compared with validated scores to predict NDAF (AS5F score, CHA2DS2-VASc [Congestive Heart Failure, Hypertension, Age ≥65 or ≥75, Diabetes, Prior Cardioembolic Event, (female) Sex, or Vascular Disease] score). CONCLUSIONS: MR-proANP is a valid biomarker to determine risk of NDAF and MACE in patients with AIS and can be used as a decision tool to identify patients for prolonged cardiac monitoring. (Biomarker Signature of Stroke Aetiology Study: The BIOSIGNAL study [BIOSIGNAL]; NCT02274727).

Seizures after Ischemic Stroke: A Matched Multicenter Study.

OBJECTIVE: The purpose of this study was to identify risk factors for acute symptomatic seizures and post-stroke epilepsy after acute ischemic stroke and evaluate the effects of reperfusion treatment. METHODS: We assessed the risk factors for post-stroke seizures using logistic or Cox regression in a multicenter study, including adults from 8 European referral centers with neuroimaging-confirmed ischemic stroke. We compared the risk of post-stroke seizures between participants with or without reperfusion treatment following propensity score matching to reduce confounding due to treatment selection. RESULTS: In the overall cohort of 4,229 participants (mean age 71 years, 57% men), a higher risk of acute symptomatic seizures was observed in those with more severe strokes, infarcts located in the posterior cerebral artery territory, and strokes caused by large-artery atherosclerosis. Strokes caused by small-vessel occlusion carried a small risk of acute symptomatic seizures. 6% developed post-stroke epilepsy. Risk factors for post-stroke epilepsy were acute symptomatic seizures, more severe strokes, infarcts involving the cerebral cortex, and strokes caused by large-artery atherosclerosis. Electroencephalography findings within 7 days of stroke onset were not independently associated with the risk of post-stroke epilepsy. There was no association between reperfusion treatments in general or only intravenous thrombolysis or mechanical thrombectomy with the time to post-stroke epilepsy or the risk of acute symptomatic seizures. INTERPRETATION: Post-stroke seizures are related to stroke severity, etiology, and location, whereas an early electroencephalogram was not predictive of epilepsy. We did not find an association of reperfusion treatment with risks of acute symptomatic seizures or post-stroke epilepsy. ANN NEUROL 2021;90:808-820.

A Panel Comprising Serum Amyloid A, White Blood Cells and Nihss for the Triage of Patients at Low Risk of Post-Stroke Infection.

Accurate and early prediction of poststroke infections is important to improve antibiotic therapy guidance and/or to avoid unnecessary antibiotic treatment. We hypothesized that the combination of blood biomarkers with clinical parameters could help to optimize risk stratification during hospitalization. In this prospective observational study, blood samples of 283 ischemic stroke patients were collected at hospital admission within 72 h from symptom onset. Among the 283 included patients, 60 developed an infection during the first five days of hospitalization. Performance predictions of blood biomarkers (Serum Amyloid-A (SAA), C-reactive protein, procalcitonin (CRP), white blood cells (WBC), creatinine) and clinical parameters (National Institutes of Health Stroke Scale (NIHSS), age, temperature) for the detection of poststroke infection were evaluated individually using receiver operating characteristics curves. Three machine learning techniques were used for creating panels: Associative Rules Mining, Decision Trees and an internal iterative-threshold based method called PanelomiX. The PanelomiX algorithm showed stable performance when applied to two representative subgroups obtained as splits of the main subgroup. The panel including SAA, WBC and NIHSS had a sensitivity of 97% and a specificity of 45% to identify patients who did not develop an infection. Therefore, it could be used at hospital admission to avoid unnecessary antibiotic (AB) treatment in around half of the patients, and consequently, to reduce AB resistance.

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

AIMS: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. METHODS AND RESULTS: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

SAA (Serum Amyloid A): A Novel Predictor of Stroke-Associated Infections.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)-a recently discovered blood biomarker-to predict poststroke infections. METHODS: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. RESULTS: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16-1.79]; P=0.001) and in study B (adjusted odds ratio, 1.52 [1.05-2.22]; P=0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69-0.83) to 0.79 (0.72-0.86; P<0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70-0.81) to 0.76 (0.71-0.82; P<0.038). CONCLUSIONS: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00390962.

Proenkephalin A Adds No Incremental Prognostic Value After Acute Ischemic Stroke.

OBJECTIVE: The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort. METHODS: The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures. RESULTS: After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33). CONCLUSION: Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.

C-Terminal-Pro-Endothelin-1 Adds Incremental Prognostic Value for Risk Stratification After Ischemic Stroke.

Background and Aims: Endothelins have shown to play a role in the pathophysiology of ischemic stroke. We aimed at evaluating the incremental prognostic value of C-terminal-pro-endothelin-1 (CT-pro-ET-1) in a well-described cohort of acute stroke patients. Methods: We performed serial measurements of CT-pro-ET-1 in 361 consecutively enrolled ischemic stroke patients and assessed functional outcome and mortality after 90 days. As we found peak levels of CT-pro-ET-1 and the most prominent association with mortality on day 1 after admission (n = 312), we focused on this time point for further outcome analyses. We calculated logistic regression and cox proportional hazards models to estimate the association of CT-pro-ET-1 with our outcome measures after adjusting for demographic and clinical risk factors. To evaluate the incremental value of CT-pro-ET-1, we calculated the area under the receiver operating characteristics (AUC) curve and the continuous net reclassification index (cNRI) comparing the model with and without the biomarker CT-pro-ET-1. Results: In the univariate analysis CT-pro-ET-1 with a peak on day 1 after admission was associated with unfavorable outcome with an OR of 1.32 (95% CI, 1.16-1.51, p < 0.001) and with mortality with a HR of 1.45 (95% CI, 1.29-1.63, p < 0.001). After adjusting, CT-pro-ET-1 remained an independent predictor of mortality with an adjusted HR of 1.50 (95% CI, 1.29-1.74, p < 0.001), but not for functional outcome. Adding CT-pro-ET-1 to the cox-regression model for mortality, the discriminatory accuracy improved from 0.89 (95% CI, 0.84-0.94) to 0.92 (95% CI, 0.88-0.96) p < 0.001, and the cNRI was 0.72 (95% CI, 0.17-1.13). Conclusion: CT-pro-ET-1 with a peak level on day 1 was an independent predictor of mortality adding incremental prognostic value beyond traditional risk factors.