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Aims: We sought to characterize circulating protein biomarkers associated with cardiogenic shock (CS) using highly multiplex proteomic profiling., Methods and Results: This analysis employed a cross-sectional case-control study design using a biorepository of patients admitted to a cardiac intensive care unit between 2017 and 2020. Cases were patients adjudicated to have CS, and controls were those presenting for cardiac critical care without shock, including subsets of patients with isolated hypotension or heart failure (HF). The Olink platform was used to analyse 359 biomarkers with Bonferroni correction. The analysis included 239 patients presenting for cardiac critical care (69 cases with CS, 170 non-shock controls). A total of 63 biomarkers (17.7%) were significantly associated with CS after Bonferroni correction compared with all controls. Of these, nine biomarkers remained significantly associated with CS when separately cross-validated in subsets of controls presenting with isolated hypotension and HF: cathepsin D, fibroblast growth factor (FGF)-21 and -23, growth differentiation factor (GDF)-15, insulin-like growth factor-binding protein-1, N-terminal pro-B-type natriuretic peptide, osteopontin, oncostatin-M-specific receptor subunit beta (OSMR), and soluble ST2 protein (sST2). Four biomarkers were identified as providing complementary information for CS diagnosis with development of a multi-marker model: sST2, FGF-23, CTSD, and GDF-15., Conclusion: In this pilot study of targeted proteomic profiling in CS, we identified nine biomarkers significantly associated with CS when cross-validated against non-shock controls including those with HF or isolated hypotension, illustrating the potential application of a targeted proteomic approach to identify novel candidates that may support the diagnosis of CS., Competing Interests: Conflict of interest: S.M.P., D.A.M., A.B., K.K.B., E.A.B., and D.D.B. are members of the TIMI Study Group that receives institutional research grant support through Brigham and Women’s Hospital from: Abbott, Abiomed, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Intarcia, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche Diagnostics, Siemens Healthcare Diagnostics, Inc., and Zora Biosciences. D.A.M. reports consulting fees from Abbott Laboratories, ARCA biopharma, InCarda, Inflammatix, Merck & Co., Novartis, and Roche Diagnostics. J.D., M.D., E.P.M., L.M., and B.O.O are employees and shareholders of Regeneron Pharmaceuticals, Inc. A.S.V. reports consulting fees from Broadview Ventures. E.A.B. reports consulting fees from Novo Nordisk, Esperion, PriMed, Medscape, Amgen, and Servier, and participation on clinical endpoint committees for studies sponsored by Kowa Pharmaceuticals. D.D.B. reports consulting fees from AstraZeneca, Mobility Bio, Inc., and Youngene Therapeutics, honoraria from the Medical Education Speakers Network (MESN) and USV Private Limited, and participation on clinical endpoint committees for studies sponsored by Beckman Coulter, Kowa Pharmaceuticals, and Tosoh Biosciences. The remaining co-authors report no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The dynamics of the sinus node response to exercise is linked to functional capacity and outcome in heart failure (HF). The goal of the work was to analyze determinants and impacts of cardio-acceleration, described by the concept of metabolic-chronotropic relation (MCR) and of cardio-deceleration, described by heart rate recovery (HRR)., Methods: A cohort of 25 healthy controls and 78 patients with advanced systolic HF and optimized medical and/or device therapy (97% receiving beta-blockers, 54% ICD) underwent maximal cardiopulmonary exercise test and were prospectively followed., Results: HF patients had impaired exercise performance compared with controls (pVO 2 15±4 vs. 29±7ml.kg -1 .min -1 , p<0.0001) and lower both MCR slope (0.54±0.24 vs. 0.90±0.15, p<0.0001) and HRR (14.7±7.9 vs. 18.3±4.2min -1 , p=0.03). In HF patients, MCR slope was inversely associated with beta-blocker dose (r=-0.24), NYHA class (r=-0.28) and HF duration (r=-0.25), whereas HRR with estimated glomerular filtration rate (eGFR, r=0.39), age (r=-0.28) and BMI (r=-0.31, all p<0.05). During a follow-up of 1269±933days, 64% patients experienced an adverse outcome (death, urgent transplantation, left ventricular assist device implantation). Those patients had higher NT-proBNP (p=0.02), worse left ventricular systolic function (LVEF, p=0.03) and lower MCR slope (p=0.02) but not HRR (p=0.19). MCR slope (but not HRR) was a significant outcome predictor (p=0.02 for Cox unadjusted model) even after adjustment for LVEF, serum natrium, systolic blood pressure, eGFR and NT-proBNP (p=0.04)., Conclusion: MCR slope is associated with different clinical variables than HRR. Compared to HRR, MCR slope provides significant prognostic information in HF patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Newer troponin assays offer the ability to quantify circulating troponin levels at an order of magnitude lower than contemporary assays, fueling continued debate over the prognostic implications of very low-level increases in concentration. We evaluated the prognostic implications of low-level increases in cardiac troponin I (cTnI) using an investigational single-molecule high-sensitivity assay in patients with acute coronary syndrome (ACS)., Methods: We measured cTnI using both a high-sensitivity troponin I (hsTnI) assay (Erenna, Singulex, 99(th) percentile 9 pg/ml) and a current generation sensitive assay (TnI-Ultra, Siemens, 99(th) percentile 40 pg/ml) at baseline in 1807 patients with non-ST elevation ACS and compared their prognostic ability for adverse cardiovascular events at 30 days and one year., Results: Among patients with TnI-Ultra<99(th) percentile, patients with elevated hsTnI (≥ 9 pg/ml) had a significantly higher risk than patients with hsTnI<9 pg/ml: cardiovascular death (CVD) or myocardial infarction (MI) at one year (7.0% vs 3.8%; p<0.001, hazard ratio (HR) 2.05, confidence interval (CI) 1.23-3.41); including a higher risk of CVD (3.5% vs 1.5%, p<0.001) and MI (5.0% vs 2.8%, p<0.001) individually. This higher risk of CVD/MI was independent of clinical risk stratification using the TIMI Risk Score (adj. HR 1.76, CI 1.05-2.90). Moreover, hsTnI showed a trend toward a gradient of risk even below the hsTnI 99 percentile., Conclusions: Low-level cardiac troponin detected using a single-molecule technique, below the cutpoint of a contemporary sensitive assay, identified a significant gradient of risk. These findings support the prognostic relevance of low-level cardiac troponin elevation with increasingly sensitive assays in patients with ACS., (© The European Society of Cardiology 2014.)

Objectives: The aim of this study was to assess the prognostic performance of C-terminal provasopressin (copeptin), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS)., Background: Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease., Methods: We measured copeptin, MR-proADM, and MR-proANP concentrations in 4,432 patients with NSTE-ACS who were randomized to treatment with ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36) trial and followed up for 1 year., Results: A high concentration (quartile 4 vs. quartiles 1 to 3) of each biomarker identified an increased risk of CV death or HF(copeptin: 13.2% vs. 5.0%, p < 0.001; MR-proADM: 15.8% vs. 4.1%, p < 0.001; MR-proANP: 17.7% vs. 3.5%, p < 0.001)as well as CV death, HF, and myocardial infarction individually (all p ≤ 0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratio: copeptin, 1.71; MR-proADM, 1.96; MR-proANP, 2.20; all p ≤ 0.001).These biomarkers improved prognostic discrimination and patient re-classification for CV death or HF at 1 year(all categorical NRI >10%, p < 0.001), and maintained independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus BNP, cTnI, ST2, PAPP-A, and MPO (each p≤0.01) [corrected]., Conclusions: Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Arginine-vasopressin (AVP) is an acute marker of physiologic stress. Copeptin is the C-terminal fragment of vasopressin precursor hormone that is more easily measured than AVP. Studies assessing the utility of copeptin in the diagnosis of myocardial infarction (MI) have demonstrated mixed results., Hypothesis: The aim of this study was to test the hypothesis that copeptin improves diagnostic performance when added to troponin for detecting MI in patients presenting to the emergency department with nontraumatic chest pain., Methods: We measured copeptin, local cardiac troponin I (local cTnI), and a contemporary sensitive cardiac troponin I (sensitive cTnI) at presentation and serially in patients who presented with acute chest pain. A copeptin cutoff of 14 pmol/L was utilized., Results: MI was diagnosed in 25.7% of patients. Noncoronary acute cardiopulmonary causes of chest pain occurred in 12.8%. Patients with MI had significantly higher copeptin levels than patients with noncardiac chest pain (P < 0.001). The area under the receiver operating characteristic curve (AUC) for copeptin was 0.60 (95% confidence interval: 0.54-0.66), significantly less than the AUC for local cTnI (0.92) or sensitive cTnI (0.96). The combination of copeptin with either the local or sensitive troponin assay (c-statistics 0.92 and 0.95, respectively) did not significantly improve the AUC as compared to either troponin assay alone. This finding persisted in the subgroup of early presenters (≤ 6 hours from symptom onset)., Conclusions: Copeptin did not improve the diagnostic performance for detecting MI when used alone or in combination with a contemporary sensitive cTnI assay, though our cohort had relatively few early presenters., (© 2014 Wiley Periodicals, Inc.)

Aims: The aim of this study is to simultaneously evaluate the incremental prognostic value of multiple cardiac biomarkers reflecting different underlying pathophysiological processes in a well-characterized population of patients with non-ST-segment acute coronary syndrome (NSTE-ACS)., Methods and Results: We measured cardiac troponin I (cTnI), N-terminal pro B-type natriuretic peptide (NT-proBNP), C-reactive protein, and myeloperodixase (MPO) among 4352 patients with NSTE-ACS in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischaemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial and followed them for a mean of 343 days. When added individually to a multivariable model adjusted for clinical characteristics, the risk of cardiovascular (CV) death rose in a stepwise fashion with increasing quartiles of each biomarker, and when using their pre-defined cut-points [HR(adj) 2.71 (P < 0.001) for cTnI ≥0.03 ng/mL; HR(adj) 3.01 (P < 0.001) for NT-proBNP ≥400 pg/mL; HR(adj) 1.45 (P = 0.019) for high-sensitivity (hs) C-reactive protein ≥15 mg/L; and HR(adj) 1.49 (P = 0.006) for MPO ≥670 pmol/L]. After including all biomarkers, only NT-proBNP and cTnI were independently associated with CV death, and only cTnI with myocardial infarction (MI). The addition of NT-proBNP to a model adjusted for TIMI risk score incorporating cTnI significantly improved both the discrimination and re-classification of the model for CV death and heart failure (HF) while there was no such improvement after the addition of either MPO or hs-C-reactive protein., Conclusion: In this study of over 4300 patients presenting with NSTEACS, we found that both cTnI and NT-proBNP offer prognostic information beyond that achieved with clinical risk variables for CV death, MI, and HF. Myeloperoxidase and hs-C-reactive protein, while independently associated with some adverse CV outcomes, did not provide substantial incremental prognostic information when evaluated together with cTnI and NT-proBNP.

Extracorporeal elimination is a method of LDL-lowering therapy that is used in severe familial hypercholesterolemia (FH) after other therapeutic approaches have failed. There are currently no universally accepted biomarkers that would allow determining necessary intensity of therapy and frequency of future therapeutic interventions. An ideal tool for immediate evaluation would be a readily measurable serum marker. We hypothesized that soluble endoglin (sCD105), a recently described indicator of endothelial dysfunction, may represent such a tool. Eleven patients with FH (three homozygous, eight heterozygous; Fredrickson type IIa, IIb) that have been monitored for 4.5+/-2.8 years were treated; eight by LDL-apheresis and three by hemorheopheresis. 40 sCD105 measurements were done, before and after two consecutive elimination procedures. Baseline serum sCD105 levels were significantly higher in the patients (5.74+/-1.47 microg/l in series I, 6.85+/-1.85 microg/l in series II) than in the control group (3.85+/-1.25 microg/l). They decreased to normal after LDL-elimination (p=0.0003) in all except for one patient. This return to normal was not due to a non-specific capture of endoglin in adsorption or filtration columns as demonstrated by measurement of sCD105 before and after passage through the elimination media. We conclude that the soluble endoglin levels in patients with severe FH remain elevated despite long-term intensive therapy and that they decrease after extracorporeal elimination. Endoglin can therefore serve as a marker for evaluation of the treatment efficacy and of the decreased atherosclerotic activity in patients with FH treated by extracorporeal LDL-cholesterol elimination.

Aim: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentrations are lower in patients with obesity. The interaction between body mass index (BMI) and NT‐proBNP with respect to heart failure risk remains incompletely defined. Methods and results: Data were pooled across three randomized clinical trials enrolling predominantly patients who were overweight or obese with established cardiometabolic disease: SAVOR‐TIMI 53, DECLARE‐TIMI 58 and CAMELLIA‐TIMI 61. Hospitalization for heart failure (HHF) was examined across strata of baseline BMI and NT‐proBNP. The effect of dapagliflozin versus placebo was assessed for a treatment interaction across BMI categories in patients with or without an elevated baseline NT‐proBNP (≥125 pg/ml). Among 24 455 patients, the median NT‐proBNP was 96 (interquartile range [IQR]: 43–225) pg/ml and the median BMI was 33 (IQR 29–37) kg/m2, with 68% of patients having a BMI ≥30 kg/m2. There was a significant inverse association between NT‐proBNP and BMI which persisted after adjustment for all clinical variables (p < 0.001). Within any range of NT‐proBNP, those at higher BMI had higher risk of HHF at 2 years (comparing BMI <30 vs. ≥40 kg/m2 for NT‐proBNP ranges of <125, 125–<450 and ≥450 pg/ml: 0.0% vs. 0.6%, 1.3% vs. 4.0%, and 8.1% vs. 13.8%, respectively), which persisted after multivariable adjustment (adjusted hazard ratio [HRadj] 7.47, 95% confidence interval [CI] 3.16–17.66, HRadj 3.22 [95% CI 2.13–4.86], and HRadj 1.87 [95% CI 1.35–2.60], respectively). In DECLARE‐TIMI 58, dapagliflozin versus placebo consistently reduced HHF across BMI categories in those with an elevated NT‐proBNP (p‐trend for HR across BMI = 0.60), with a pattern of greater absolute risk reduction (ARR) at higher BMI (ARR for BMI <30 to ≥40 kg/m2: 2.2% to 4.7%; p‐trend = 0.059). Conclusions: The risk of HHF varies across BMI categories for any given range of circulating NT‐proBNP. These findings showcase the importance of considering BMI when applying NT‐proBNP for heart failure risk stratification, particularly for patients with low‐level elevations in NT‐proBNP (125–<450 pg/ml) where there appears to be a clinically meaningful absolute and relative risk gradient. [ABSTRACT FROM AUTHOR]

Aims: Cardiac functional and structural remodelling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. Methods and results: ENGAGE AF‐TIMI 48 was a randomized trial of edoxaban versus warfarin in 21 105 patients with AF. We performed a nested biomarker study, analysing high‐sensitivity troponin T (hsTnT, n = 8705), N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP, n = 8765), and growth differentiation factor‐15 (GDF‐15, n = 8705) at baseline and 12 months. Of the biomarker cohort, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly reduced EF (HFmrEF; 40–49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT‐proBNP, and GDF‐15 were associated with higher risk of hospitalization for HF (HHF) or HF death overall and in subpopulations defined by HF history and EF (p < 0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (p‐interaction >0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF or HF death in the overall population (p < 0.001 for each biomarker and category). Conclusion: Serial measurement of hsTnT, NT‐proBNP, and GDF‐15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF. Clinical Trial Registration: ClinicalTrials.gov unique identifier NCT00781391. [ABSTRACT FROM AUTHOR]

To assess changes in SARS-CoV-2 spike binding antibody prevalence in the Dominican Republic and implications for immunologic protection against variants of concern, we prospectively enrolled 2,300 patients with undifferentiated febrile illnesses in a study during March 2021-August 2022. We tested serum samples for spike antibodies and tested nasopharyngeal samples for acute SARS-CoV-2 infection using a reverse transcription PCR nucleic acid amplification test. Geometric mean spike antibody titers increased from 6.6 (95% CI 5.1-8.7) binding antibody units (BAU)/mL during March-June 2021 to 1,332 (95% CI 1,055-1,682) BAU/mL during May-August 2022. Multivariable binomial odds ratios for acute infection were 0.55 (95% CI 0.40-0.74), 0.38 (95% CI 0.27-0.55), and 0.27 (95% CI 0.18-0.40) for the second, third, and fourth versus the first anti-spike quartile; findings were similar by viral strain. Combining serologic and virologic screening might enable monitoring of discrete population immunologic markers and their implications for emergent variant transmission. [ABSTRACT FROM AUTHOR]

Aims Patients with obesity frequently present with dyspnoea. Biomarkers that reflect wall stress are often used to evaluate circulatory congestion and help determine whether dyspnoea is of cardiac causes. Patients with obesity display greater external restraint on the heart, which may alter relationships between intravascular pressures and stress markers. Methods and results Subjects with unexplained dyspnoea (n =212) underwent cardiac catheterization with simultaneous echocardiography. Blood sampling was performed in a subset (n =58). Relationships between echocardiographic and blood biomarkers of circulatory congestion and directly-measured haemodynamics were compared between participants with severe obesity [body mass index (BMI)=35 kg/m2, Group B) and those without (BMI<35 kg/m2, Group A). Circulatory congestion was assessed by pulmonary capillary wedge pressure (PCWP), and vascular distending pressure was assessed by left ventricular transmural pressure (LVTMP). As compared to Group A, participants in Group B displayed higher PCWP relative to N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide, troponin T, and growth differentiation factor-15 (all p <0.01). In contrast, the relationships between LVTMP and the biomarkers were superimposable. Echocardiographic biomarkers revealed the same pattern: PCWP was higher for any E/e' ratio in Group B compared to Group A, but the relationship between LVTMP and E/e' was similar. In contrast, levels of C-terminal pro-endothelin-1 and mid-regional pro-adrenomedullin were more robustly correlated with PCWP (r = 0.67 and r = 0.62, both p <0.0001), with no differential relationship based upon BMI. Conclusions Non-invasive haemodynamic markers underestimate circulatory congestion in patients with obesity, an effect that appears related to uncoupling between cardiac wall stress and intravascular pressures. This may lead to systematic under-recognition of congestion in patients with obesity. [ABSTRACT FROM AUTHOR]

Aims We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding. Methods and results ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36–2.23 and adj-HR 1.27; 95% CI 1.07–1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02–1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36–0.65; NRI 0.42; 95% CI 0.33–0.51, respectively]. Conclusion Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF. [ABSTRACT FROM AUTHOR]

Objective. To determine the proportion of initial troponin (cTn) elevations associated with Type I MI versus other cardiovascular and noncardiovascular diagnoses in an emergency department (ED) and whether or not a relationship exists between the cTn level and the likelihood of Type I MI. Background. In the ED, cTn is used as a screening test for myocardial injury. However, the differential diagnosis for an initial positive cTn result is not clear. Methods. Hospital medical records were retrospectively reviewed for visits associated with an initial positive troponin I-ultra (cTnI), ≥0.05 μg/L. Elevated cTnI levels were stratified into low (0.05–0.09), medium (0.1–0.99), or high (≥1.0). Discharge diagnoses were classified into 3 diagnostic groups (Type I MI, other cardiovascular, or noncardiovascular). Results. Of 23,731 ED visits, 4,928 (21%) had cTnI testing. Of those tested, 16.3% had initial cTnI ≥0.05. Among those with elevated cTn, 11% were classified as Type I MI, 34% had other cardiovascular diagnoses, and 55% had a noncardiovascular diagnosis. Type I MI was more common with high cTnI levels (41% incidence) than among subjects with medium (9%) or low (6%). Conclusion. A positive cTn is most likely a noncardiovascular diagnosis, but Type I MI is far more common with cTnI levels ≥1.0. [ABSTRACT FROM AUTHOR]

Cardiac troponins I and T are established biomarkers of cardiac injury. Testing for either of these two cardiac troponins has long been an essential component of the diagnosis of acute myocardial infarction. In addition, cardiac troponin concentrations after acute myocardial infarction predict future adverse events including development of ischemic heart failure and chronic elevations of cardiac troponin correlate with heart failure severity. These predictions and correlations are particularly obvious when cardiac troponin concentrations are measured using the new high sensitivity cardiac troponin assays. Thus, a growing body of literature suggests that cardiac troponin testing may have important clinical implications for heart failure patients with reduced or preserved ejection fraction. In this review, we explore the prognostic utility of measuring cardiac troponin concentrations in patients with acute or chronic heart failure and in populations at risk of developing heart failure and the relationship between cardiac troponin levels and disease severity. We also summarize the ongoing debates and research on whether serial monitoring of cardiac troponin levels may become a useful tool for guiding therapeutic interventions in patients with heart failure. [ABSTRACT FROM AUTHOR]

Abstract: The incidence of heart failure has been steadily increasing over the past several decades. High readmission rates in patients with acute decompensated heart failure led to the search for biomarkers that could predict future clinical course and would, in an ideal case, enable monitoring of patients with heart failure and guidance of their therapy. From among several promising markers, the B-type natriuretic peptide and the biologically inactive N-terminal portion of its pro-hormone, NT-proBNP, have become the most frequently used analytes. Other known markers, such as atrial natriuretic peptide and endothelin-1, are currently used for research purposes. The development of additional biomarkers will be an important step from improving diagnosis and treatment of patients with chronic and acute decompensated heart failure. [Copyright &y& Elsevier]

Supplemental Digital Content is available in the text. Background: Spironolactone has been demonstrated to reduce heart failure (HF) hospitalization in patients with HF with preserved ejection fraction in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We assessed effects of 12 months of treatment with spironolactone on biomarkers reflecting myocardial stress, myocardial injury, renal function, and systemic inflammation. Methods: This TOPCAT biorepository substudy evaluated 247 patients (14% of the total 1767 patients in the Americas region) with symptomatic HF, ejection fraction ≥45%, and elevated natriuretic peptides or a prior HF hospitalization. Paired blood samples at baseline and after 12 months of treatment with spironolactone or placebo were available in 204 patients. Results: At baseline, the median (interquartile range) concentration of BNP (B-type natriuretic peptide) was 124 (69–197) ng/L, NT-proBNP (N-terminal-pro-B-type natriuretic peptide) 624 (307–1312) ng/L, hs-cTnI (high sensitivity cardiac troponin I) 6.3 (3.4–13.0) ng/L, hs-CRP (high sensitivity C-reactive protein) 2.8 (1.3–6.1) mg/L, uric acid 7.2 (5.8–8.7) mg/dL, and urine protein-creatinine ratio 0.11 (0.08–0.20) mg/mg. Compared with placebo-assigned participants at 12 months, those randomized to spironolactone experienced greater reductions from baseline in levels of NT-proBNP (P =0.017) and BNP (P =0.002); these differences persisted after adjustment for demographics, comorbidities, estimated glomerular filtration rate, and enrollment strata. No between-group differences in changes in hs-cTnI, CRP, uric acid, or urine protein-creatinine ratio were observed. Conclusions: This TOPCAT biorepository substudy suggests potential effects on markers of cardiac wall stress or filling pressures during 12 months of treatment with spironolactone in patients with chronic HF with preserved ejection fraction. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Levels of cTn (cardiac troponin) are frequently elevated in patients with heart failure (HF) and reduced ejection fraction (EF) and correlate with the risk for mortality. However, factors associated with high cTn concentrations and the association with cardiovascular events in patients with HF and preserved EF are unclear. Methods and Results: Of 1767 subjects with symptomatic HF with preserved EF from the Americas part of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial), 236 underwent baseline measurements of high-sensitivity (hs) cTnI using the Abbott Architect STAT assay. Baseline factors correlated with hs-cTnI levels were assessed in stepwise linear regression models and the association between hs-cTnI and adjudicated study outcomes was examined in Cox models. The median hs-cTnI concentration at baseline was 6.3 ng/L (interquartile range, 3.4–12.9 ng/L) with levels detectable in 99.2% of patients. Higher hs-cTnI concentrations were associated with male sex, black race, lower estimated glomerular filtration rate and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. After multivariable adjustment, higher concentrations of hs-cTnI were associated with greater risk for the composite of cardiovascular death or HF hospitalization (69 events during mean follow-up 2.6±1.5 years): hazard ratio 1.42 (95% CI, 1.20–1.69), P <0.001 per doubling of hs-cTnI. Compared with those in the lowest quartile of hs-cTnI, patients in the highest quartile demonstrated a nearly 5-fold higher risk of cardiovascular death and HF hospitalization (hazard ratio 4.85 [1.99–11.83], P =0.001). There was no interaction between hs-cTnI and spironolactone treatment with regard to the primary composite end point (interaction P =0.94). Conclusions: In ambulatory patients with HF with preserved EF, levels of hs-cTnI are higher in male patients with black race, lower estimated glomerular filtration rate, and higher NT-proBNP. As in those with HF and reduced EF, higher hs-cTnI levels are independently associated with risk for cardiovascular death and HF hospitalization. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302. [ABSTRACT FROM AUTHOR]

Background: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain.Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA2DS2-VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores.Results: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA2DS2-VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA2DS2-VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin.Conclusions: The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA2DS2-VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391. [ABSTRACT FROM AUTHOR]

Background: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). Methods: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level. Results: Overall, 3048 participants had baseline ET-1 measurements: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28–4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53–2.50] for T3 and 1.36 [95% CI, 1.06–1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, –3.19 [95% CI, –3.66 to –2.72] mL/min per 1.73 m2 per y, T2, –2.08 [95% CI, –2.52 to –1.63] and T1 –2.35 [95% CI, –2.79 to –1.91]; P =0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25–0.01; P =0.029). Conclusions: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. Background: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. Methods: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. Results: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function. Conclusions: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558) [Copyright &y& Elsevier]

Background: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels.Methods: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction ≤40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored.Results: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076).Conclusions: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124. [ABSTRACT FROM AUTHOR]

Background: The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.Objectives: The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.Methods: Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.Results: A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.Conclusions: The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers. [ABSTRACT FROM AUTHOR]

Introduction: When used in combination with clinical risk factors, circulating biomarkers of underlying cardiovascular disease may improve prediction of stroke/systemic embolism (S/SEE) and bleeding in patients (pts) with atrial fibrillation (AF). Hypothesis: Biomarker based risk scores incorporating high-sensitivity (hs)TnT, NT-proBNP, and growth differentiation factor (GDF)-15 will improve discrimination compared with established clinical scores. Methods: ENGAGE AF-TIMI 48 was a multinational, randomized, double-blind trial of the oral factor Xa inhibitor edoxaban in pts with AF and CHADS2 score of ≥2. We performed a nested prospective biomarker study in 8705 pts, analyzing baseline hsTnT, NT-proBNP, and GDF-15 (Roche Diagnostics) using a priori cutpoints. Variables from the published ABC-stroke (age, prior stroke/TIA, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. The endpoints of S/SEE and ISTH major bleeding were centrally adjudicated. Hazard ratios (HRs) were adjusted for age, sex, renal function, history of HF, HTN, DM, CAD, PAD, and stroke/TIA. Results: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L, 811 pg/mL, and 1661 pg/mL, respectively. Both hsTnT and NT-proBNP were independently associated with higher rates of S/SEE (Fig-left , p<0.01 for each). In addition, both GDF-15 and hsTnT were independently associated with higher risk of bleeding (Fig-right , p<0.01). The ABC-stroke and ABC-bleeding risk scores re-estimated in this cohort yielded higher c-indices than the CHA2DS2-VASc (0.67 vs. 0.57; p<0.01) and HAS-BLED (0.70 vs. 0.59; p<0.01) scores, respectively. Conclusions: CV biomarkers (hsTnT, NT-proBNP, and GDF-15) add to clinical risk indicators for assessing the risk of S/SEE and major bleeding in pts with AF. Incorporating these biomarkers into clinical risk scores may aid in assessment of pts with AF considering anticoagulation. [ABSTRACT FROM AUTHOR]

Background: Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown.Objectives: This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients.Methods: In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe.Results: Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (ptrend < 0.001 for each). There was a pattern of greater absolute risk reduction in CV death/myocardial infarction/stroke with the addition of ezetimibe to statin therapy in patients at higher risk on the basis of biomarker levels. High-risk patients (≥3 biomarkers "positive"; n = 1,437) had an absolute risk difference of -7.3% (95% confidence interval: -13.8% to -0.8%; p = 0.02) with ezetimibe, and intermediate-risk patients (1 to 2 biomarkers positive; n = 3,842) had an absolute risk difference of -4.4% (95% confidence interval: -9.7% to 0.8%), translating into numbers needed to treat at 7 years of 14 and 23, respectively. Low-risk patients (0 biomarkers positive; n = 1,916) did not appear to benefit from the addition of ezetimibe to statin therapy.Conclusions: A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy. [ABSTRACT FROM AUTHOR]

Background: Cardiac reserve is depressed in patients with heart failure and preserved ejection fraction (HFpEF). The mechanisms causing this are poorly understood.Objectives: The authors hypothesized that myocardial injury might contribute to the hemodynamic derangements and cardiac reserve limitations that are present in HFpEF. Markers of cardiomyocyte injury, central hemodynamics, ventricular function, and determinants of cardiac oxygen supply-demand balance were measured.Methods: Subjects with HFpEF (n = 38) and control subjects without heart failure (n = 20) underwent cardiac catheterization, echocardiography, and expired gas analysis at rest and during exercise. Central venous blood was sampled to measure plasma high-sensitivity troponin T levels as an index of cardiomyocyte injury.Results: Compared with control subjects, troponins were more than 2-fold higher in subjects with HFpEF at rest and during exercise (p < 0.0001). Troponin levels were directly correlated with left ventricular (LV) filling pressures (r = 0.52; p < 0.0001) and diastolic dysfunction (r = -0.43; p = 0.002). Although myocardial oxygen demand was similar, myocardial oxygen supply was depressed in HFpEF, particularly during exercise (coronary perfusion pressure-time integral; 44 ± 9 mm Hg × s × min-1 × l × dl-1 vs. 30 ± 9 mm Hg × s × min-1 × l × dl-1; p < 0.0001), and reduced indices of supply were correlated with greater myocyte injury during exercise (r = -0.44; p = 0.0008). Elevation in troponin with exercise was directly correlated with an inability to augment LV diastolic (r = -0.40; p = 0.02) and systolic reserve (r = -0.57; p = 0.0003), greater increases in LV filling pressures (r = 0.55; p < 0.0001), blunted cardiac output response (r = -0.44; p = 0.002), and more severely depressed aerobic capacity in HFpEF.Conclusions: Limitations in LV functional reserve and the hemodynamic derangements that develop secondary to these limitations during exercise in HFpEF are correlated with the severity of cardiac injury, assessed by plasma levels of troponin T. Further study is warranted to determine the mechanisms causing myocyte injury in HFpEF and the potential role of ischemia, and to identify and test novel interventions targeted to these mechanisms. (EXEC [Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease]; NCT01418248). [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the prognostic performance of C-terminal provasopressin (copeptin), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS). Background: Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease. Methods: We measured copeptin, MR-proADM, and MR-proANP concentrations in 4,432 patients with NSTE-ACS who were randomized to treatment with ranolazine or placebo in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36) trial and followed up for 1 year. Results: A high concentration (quartile 4 vs. quartiles 1 to 3) of each biomarker identified an increased risk of CV death or HF (copeptin: 13.2% vs. 5.0%, p > 0.001; MR-proADM: 15.8% vs. 4.1%, p > 0.001; MR-proANP: 17.7% vs. 3.5%, p > 0.001) as well as CV death, HF, and myocardial infarction individually (all p ≤ 0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratio: copeptin, 1.71; MR-proADM, 1.96; MR-proANP, 2.20; all p ≤ 0.001). These biomarkers improved prognostic discrimination and patient reclassification for CV death or HF at 1 year (all categorical net reclassification improvement: <10%; p > 0.001) and maintained an independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus B-type natriuretic peptide, cardiac troponin I, ST2, pregnancy-associated plasma protein A, and myeloperoxidase (each p ≤ 0.01). Conclusions: Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788) [Copyright &y& Elsevier]

Background--Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy. Methods and Results--We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Convening Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; Pinteraction=0.012). Conclusions--In patients with stable coronary artery disease and preserved left ventricular election fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy. [ABSTRACT FROM AUTHOR]