Cardiac Troponin T and NT-proBNP for Prediction of 30-Day Readmission or Death in Patients with Acute Dyspnea: Data from the Akershus Cardiac Examination 2 Study.

INTRODUCTION: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) measurements are recommended in patients with acute dyspnea. We aimed to assess the prognostic merit of cTnT compared to NT-proBNP for 30-day readmission or death in patients hospitalized with acute dyspnea. METHODS: We measured cTnT and NT-proBNP within 24 h in 314 patients hospitalized with acute dyspnea and adjudicated the cause of the index admission. Time to first event of readmission or death ≤30 days after hospital discharge was recorded, and cTnT and NT-proBNP measurements were compared head-to-head. RESULTS: Patients who died (12/314) or were readmitted (71/314) within 30 days had higher cTnT concentrations (median: 32.6, Q1-Q3: 18.4-74.2 ng/L vs. median: 19.4, Q1-Q3: 8.4-36.1 ng/L; p for comparison <0.001) and NT-proBNP concentrations (median: 1,753.6, Q1-Q3: 464.2-6,862.0 ng/L vs. median 984, Q1-Q3 201-3,600 ng/L; for comparison p = 0.027) compared to patients who survived and were not readmitted. cTnT concentrations were associated with readmission or death within 30 days after discharge both in the total cohort (adjusted hazard ratio [aHR]: 1.64, 95% confidence interval [CI]: 1.30-2.05) and in patients with heart failure (HF) (aHR: 1.58, 95% CI: 1.14-2.18). In contrast, NT-proBNP concentrations were not associated with short-term events, neither in the total cohort (aHR: 1.10, 95% CI: 0.94-1.30) nor in patients with adjudicated HF (aHR: 1.06, 95% CI: 0.80-1.40). CONCLUSION: cTnT concentrations are associated with 30-day readmission or death in patients hospitalized with acute dyspnea, as well as in patients adjudicated HF.

Circulating MicroRNA-210 Concentrations in Patients with Acute Heart Failure: Data from the Akershus Cardiac Examination 2 Study.

BACKGROUND: MicroRNA (miR)-210 expression is induced by acute and chronic hypoxia and provides prognostic information in patients with aortic stenosis and acute coronary syndrome. We hypothesized that circulating miR-210 concentrations could provide diagnostic and prognostic information in patients with acute heart failure (HF). METHODS: We measured miR-210 concentrations in serum samples on admission from 314 patients hospitalized for acute dyspnea and 9 healthy control subjects. The diagnostic and prognostic properties of miR-210 were tested in patients after adjudication of all diagnoses and with median follow-up of 464 days. RESULTS: All patients and control subjects had miR-210 concentrations within the range of detection, and the analytical variation was low as the coefficient of variation of synthetic spike-in RNA was 4%. Circulating miR-210 concentrations were increased in patients with HF compared to healthy control subjects, but miR-210 concentrations did not separate patients with acute HF (n = 143) from patients with non-HF-related dyspnea (n = 171): the area under the curve was 0.50 (95% CI 0.43-0.57). Circulating miR-210 concentrations were associated with mortality (n = 114) after adjustment for clinical risk factors (hazard ratio 1.65 [95% CI 1.03-2.62] per unit miR-210 increase), but this association was attenuated and not significant after adjustment for established cardiac protein biomarkers. CONCLUSIONS: Circulating miR-210 concentrations are associated with mortality, but do not add to established protein biomarkers for diagnosis or prognosis in patients with acute dyspnea.

Performance of a Novel Research-Use-Only Secretoneurin ELISA in Patients with Suspected Acute Coronary Syndrome: Comparison with an Established Secretoneurin Radioimmunoassay.

BACKGROUND: Circulating secretoneurin (SN) concentrations, as measured by established radioimmunoassay (RIA), risk stratify patients with cardiovascular disease. We now report data for a recently developed research-use-only SN enzyme-linked immunosorbent assay (ELISA) in patients with suspected acute coronary syndrome (ACS). METHODS: SN ELISA was developed according to industry standards and tested in 401 unselected chest pain patients. Blood samples were drawn <24 h from admission, and we adjudicated all hospitalizations as ACS or non-ACS. The mean follow-up was 6.2 years. RESULTS: SN ELISA with 2 monoclonal sheep anti-SN antibodies has a measuring range of 10-250 pmol/L and demonstrates excellent analytical precision and accuracy across the range of SN concentrations. SN measured by ELISA and RIA correlated in the chest pain patients: rho = 0.39, p < 0.001. SN concentrations were higher in ACS patients (n = 161 [40%]) than in non-ACS patients (n = 240) for both assays, with an area under the curve (AUC) of 0.66 (95% CI: 0.61-0.71) for ELISA and 0.59 (0.54-0.65) for RIA. SN concentrations were also higher in nonsurvivors (n = 65 [16%]) than survivors, with an AUC of 0.72 (0.65-0.79) for ELISA versus 0.64 (0.56-0.72) for RIA, p = 0.007, for difference between assays. Adjusting for age, sex, blood pressure, previous myocardial infarction, atrial fibrillation, and heart failure in multivariable analysis, SN concentrations as measured by ELISA, but not RIA, remained associated with mortality, with a hazard ratio of 1.71 (1.03-2.84), p = 0.038. CONCLUSIONS: The novel SN ELISA has excellent performance, higher AUC for diagnosis, and superior prognostic accuracy compared to the established RIA in chest pain patients.

Prognostic and diagnostic significance of mid-regional pro-atrial natriuretic peptide in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 Study.

PURPOSE: To compare the diagnostic and prognostic value of mid-regional pro-ANP (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea. METHODS: MR-proANP and NT-proBNP were measured with commercial immunoassays at hospital admission (n = 313), on day 2 (n = 234), and before discharge (n = 91) and compared for diagnosing acute heart failure (HF; n = 143) and to predict mortality among patients with acute HF and acute exacerbation of chronic obstructive pulmonary disease (AECOPD; n = 84) separately. RESULTS: The correlation coefficient between MR-proANP and NT-proBNP was 0.89 (p < 0.001) and the receiver-operating area under the curve (AUC) was 0.85 (95% CI 0.81-0.89) for MR-proANP and 0.86 (0.82-0.90) for NT-proBNP to diagnose acute HF. During a median follow-up of 816 days, mortality rates were 46% in acute HF patients and 42% in AECOPD patients. After adjustment for other risk variables by multivariate Cox regression analysis, MR-proANP and NT-proBNP concentrations were associated with mortality in patients with acute HF, but only MR-proANP were associated with mortality among patients with AECOPD: hazard ratio (lnMR-proANP) 1.98 (95% CI 1.17-3.34). CONCLUSION: MR-proANP and NT-proBNP concentrations provide similar diagnostic and prognostic information in patients with acute HF. In contrast to NT-proBNP, MR-proANP measurements also provided independent prognostic information in AECOPD patients.

Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 study.

BACKGROUND: Copeptin is a novel biomarker that predicts mortality in lower respiratory tract infections and heart failure (HF), but the diagnostic value of copeptin in acute dyspnea and the prognostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not clear. METHOD: We determined copeptin and NT-proBNP concentrations at hospital admission in 314 patients with acute dyspnea who were categorized by diagnosis. Survival was registered after a median follow-up of 816 days, and the prognostic and diagnostic properties of copeptin and NT-proBNP were analyzed in acute HF (n = 143) and AECOPD (n = 84) separately. RESULTS: The median concentration of copeptin at admission was lower in AECOPD compared to acute HF (8.8 [5.2-19.7] vs. 22.2 [10.2-47.9]) pmol/L, p < 0.001), but NT-proBNP discriminated acute HF from non-HF related dyspnea more accurately than copeptin (ROC-AUC 0.85 [0.81-0.89] vs. 0.71 [0.66-0.77], p < 0.0001). Adjusted for basic risk factors, increased copeptin concentrations predicted mortality in AECOPD (HR per log (ln) unit 1.72 [95% CI 1.21-2.45], p = 0.003) and acute HF (1.61 [1.25-2.09], p < 0.001), whereas NT-proBNP concentrations predicted mortality only in acute HF (1.62 [1.27-2.06], p < 0.001). On top of a basic model copeptin reclassified a significant proportion of patients into a more accurate risk strata in AECOPD (NRI 0.60 [0.19-1.02], p = 0.004) and acute HF (0.39 [0.06-0.71], p = 0.020). CONCLUSION: Copeptin is a strong prognostic marker in both AECOPD and acute HF, while NT-proBNP concentrations predict mortality only in patients with acute HF. NT-proBNP levels are superior to copeptin levels to diagnose acute HF in patients with acute dyspnea.

The influence of heart failure co-morbidity on high-sensitivity troponin T levels in COPD exacerbation in a prospective cohort study: data from the Akershus cardiac examination (ACE) 2 study.

CONTEXT: Troponin (hs-TnT) levels predict mortality after acute exacerbation of COPD (AECOPD). Whether this is independent of heart failure (HF) is not established. MATERIAL AND METHODS: Prospectively included AECOPD patients adjudicated for acute HF categorized into three groups: (A) AECOPD, but acute HF the primary cause for hospitalization; (B) AECOPD the primary cause, but co-existing myocardial dysfunction and (C) AECOPD without myocardial dysfunction. RESULTS: About 103 AECOPD patients; 18% A, 27% B and 54% C. Hs-TnT level differed between the groups: (ng/l, median) A: 41, B: 25 and C: 15, p = 0.03 for A versus B and p = 0.005 for B versus C. During a median 826 days, 47% died. In Cox analysis, hs-TnT levels remained associated with mortality (hazard ratio per 10 ng/l 1.3, p < 0.0001). CONCLUSION: hs-TnT levels are influenced by myocardial dysfunction/HF in AECOPD, but provide independent prognostic information. The prognostic merit of hs-TnT cannot be attributed to HF alone.

Influence of glycosylation on diagnostic and prognostic accuracy of N-terminal pro-B-type natriuretic peptide in acute dyspnea: data from the Akershus Cardiac Examination 2 Study.

BACKGROUND: The N-terminal part of pro-B-type natriuretic peptide (NT-proBNP) is glycosylated, but whether glycosylation influences the diagnostic and prognostic accuracy of NT-proBNP measurements is not known. METHODS: We measured NT-proBNP concentrations of 309 patients with acute dyspnea by use of standard EDTA tubes and EDTA tubes pretreated with deglycosylation enzymes. The primary cause of dyspnea was classified as heart failure (HF) or non-HF, and the diagnosis was adjudicated by 2 independent physicians. We collected information on all-cause mortality during follow-up. RESULTS: In all, 142 patients (46%) were diagnosed with HF. NT-proBNP concentrations in nondeglycosylated samples distinguished HF patients from patients with non-HF related dyspnea [median 3588 (quartiles 1-3 1578-8404) vs 360 (126-1139) ng/L, P < 0.001], but concentrations were markedly higher in samples pretreated with deglycosylation enzymes (total NT-proBNP) [7497 (3374-14 915) vs 798 (332-2296) ng/L, P < 0.001]. The AUC to separate HF patients from patients with non-HF related dyspnea was 0.871 (95% CI 0.829-0.907) for total NT-proBNP compared with 0.852 (0.807-0.890) for NT-proBNP measurements in standard EDTA plasma. During a median follow-up of 816 days, 112 patients (36%) died. Both NT-proBNP and total NT-proBNP concentrations were associated with mortality in separate multivariate models, but only total NT-proBNP concentrations provided added value to the basic risk model of our dataset as assessed by the net reclassification index: 0.24 (95% CI 0.003-0.384). There was a graded increase in risk across total NT-proBNP quartiles, in contrast with the results for NT-proBNP measurements. CONCLUSIONS: NT-proBNP concentrations were higher, and diagnostic and prognostic accuracy was improved, by pretreating tubes with deglycosylation enzymes.

Osteoprotegerin concentrations in patients with suspected reversible myocardial ischemia: observations from the Akershus Cardiac Examination (ACE) 1 Study.

Increased circulating osteoprotegerin (OPG) levels have been associated with the prevalence and severity of coronary artery disease and the risk of cardiovascular death. OPG is a cytokine of the tumor necrosis factor receptor superfamily and is expressed in various cell types in the body, including osteoblasts, inflammatory cells, vascular smooth muscle cells/endothelial cells and cardiomyocytes. The main sources determining OPG levels in the circulation however, are not well understood, and whether reversible myocardial ischemia influences OPG levels are not known. Accordingly, OPG levels were measured in 198 patients referred for exercise stress testing and myocardial perfusion imaging (MPI). In addition OPG levels were measured in 8 healthy control subjects performing a maximal bicycle stress test. Plasma samples were collected before, immediately after, 1.5h and 4.5h after exercise stress testing with MPI. OPG levels at baseline were not different in patient with reversible myocardial ischemia (n=19) and patients without reversible ischemia (n=179) (4.7 [3.6-5.5]pmol/L vs. 4.3 [3.4-5.2]pmol/L, p=0.21), and there was an increase in OPG levels immediately after exercise regardless of whether or not the patient had reversible ischemia on MPI (absolute increase: 0.2 [0-0.55]pmol/L vs. 0.3 [0-0.5]pmol/L, p=0.72). OPG levels also increased immediately after stress in the 8 control subjects (3.5 (3.2-3.8)pmol/L at baseline to 3.8 (3.5-4.7), p=0.008). In conclusion, OPG levels increase acutely during exercise stress testing, but this increase is likely caused by mechanisms other than myocardial ischemia.

[Diagnostic accuracy for heart failure ­ data from the Akershus Cardiac Examination 2 Study]. / Diagnostisk treffsikkerhet for hjertesvikt ­ data fra Akershus hjerteundersøkelse 2.

BACKGROUND: Diagnosing heart failure in an on-call setting can be difficult, and international studies report diagnostic accuracy among duty doctors, as measured using area under the ROC curve (AUC), to be 0.76-0.90. This study has examined the accuracy with which doctors in the internal medicine out-of-hours service in a Norwegian university hospital distinguish heart failure from no heart failure in patients with dyspnoea. MATERIAL AND METHOD: Information was gathered on 468 patients admitted to Akershus University Hospital with dyspnoea between June 2009 and November 2010, and 314 patients were included in the study. The duty doctors estimated the probability of heart failure (0-100%) before N-terminal pro-B-type natriuretic peptide (NTproBNP) concentrations were known. The final diagnosis for the hospital admission was made retrospectively by two independent doctors after review of the medical records, including supplementary tests and the patient outcome. RESULTS: Heart failure was considered the cause of hospitalisation in 143 patients (46%). Patients with heart failure were older, more often men, had a higher prevalence of heart disease, reduced/impaired renal function, and higher NTproBNP concentrations than patients with non-heart failure dyspnoea. The diagnostic accuracy among duty doctors for heart failure (AUC) was 0.86 (95% confidence interval 0.82-0.90). The doctors' diagnostic accuracy was lower when the patient had heart failure with left ventricular ejection fraction [LVEF] ≥ 50% (n=52): AUC 0.83 (0.77-0.87). INTERPRETATION: The duty doctors at Akershus University Hospital from 2009-2010 demonstrated similar diagnostic accuracy for heart failure as previously reported from international centres. Diagnostic accuracy was lower for heart failure patients with LVEF ≥ 50%.

Troponin I measured by a high-sensitivity assay in patients with suspected reversible myocardial ischemia: data from the Akershus Cardiac Examination (ACE) 1 study.

BACKGROUND: Whether cardiac troponin concentrations are increased by reversible myocardial ischemia is controversial. Differences in the structure of cardiac troponin I (cTnI) and cTnT may have implications for diagnostic utility. METHODS: cTnI was measured with a prototype high-sensitivity (hs) assay in 198 patients referred for myocardial perfusion imaging (MPI) before exercise stress testing, immediately after, and 1.5 and 4.5 h later. We categorized patients according to MPI results and compared hs-cTnI concentrations with hs-cTnT concentrations. RESULTS: Baseline hs-cTnI was higher in patients with reversible myocardial ischemia (n = 19) vs the other patients (n = 179): median 4.4 (quartiles 1-3: 2.3-7.1) vs 2.5 (1.4-4.3) ng/L, P = 0.003. Baseline hs-cTnI and hs-cTnT concentrations were correlated (r = 0.46, P < 0.001) and the areas under the ROC curve for hs-cTnI and hs-cTnT in diagnosing reversible ischemia were similar: 0.71 vs 0.69, P = 0.77. Whereas hs-cTnI increased immediately after exercise (P < 0.001 vs baseline measurements) in patients without ischemia, it increased after 4.5 h in patients with reversible ischemia (P = 0.01). The increment in hs-cTnI concentrations was comparable between groups; thus, measuring hs-cTnI after exercise stress testing did not improve diagnostic accuracy over baseline measurements, and hs-cTnI concentrations were not found to be associated with reversible myocardial ischemia in multivariate analysis. By linear regression analysis, age, male sex, history of hypertension, angiotensin-converting enzyme inhibitor use, and lower left ventricular ejection fraction were associated with higher baseline hs-cTnI concentrations. CONCLUSIONS: In patients referred to MPI, hs-cTnI concentrations were not closely associated with reversible myocardial ischemia, but rather were influenced by variables associated with structural alterations of the myocardium.

NT-proBNP independently predicts long term mortality after acute exacerbation of COPD - a prospective cohort study.

BACKGROUND: Cardiovascular disease is prevalent and frequently unrecognized in patients with chronic obstructive pulmonary disease (COPD). NT-proBNP is an established risk factor in patients with heart failure. NT-proBNP may also be released from the right ventricle. Thus serum NT-proBNP may be elevated during acute exacerbations of COPD (AECOPD). The prognostic value of NT-proBNP in patients hospitalized with AECOPD is sparsely studied. Our objective was to test the hypothesis that NT-proBNP independently predicts long term mortality following AECOPD. METHODS: A prospective cohort study of 99 patients with 217 admissions with AECOPD. Clinical, electrocardiographic, radiological and biochemical data were collected at index and repeat admissions and analyzed in an extended survival analysis with time-dependent covariables. RESULTS: Median follow-up time was 1.9 years, and 57 patients died during follow-up. NT-proBNP tertile limits were 264.4 and 909 pg/mL, and NT-proBNP in tertiles 1 through 3 was associated with mortality rates of 8.6, 35 and 62 per 100 patient-years, respectively (age-adjusted log-rank p<0.0001). After adjustment for age, gender, peripheral edema, cephalization and cTnT in a multivariable survival model, the corresponding hazard ratios for dying were 2.4 (0.95-6.0) and 3.2 (1.3-8.1) (with 95% confidence intervals in parentheses, p-value for trend 0.013). CONCLUSIONS: NT-proBNP is a strong and independent determinant of mortality after AECOPD.

Cardiac troponin T levels and exercise stress testing in patients with suspected coronary artery disease: the Akershus Cardiac Examination (ACE) 1 study.

Whether reversible ischaemia in patients referred for exercise stress testing and MPI (myocardial perfusion imaging) is associated with changes in circulating cTn (cardiac troponin) levels is controversial. We measured cTnT with a sensitive assay before, immediately after peak exercise and 1.5 and 4.5 h after exercise stress testing in 198 patients referred for MPI. In total, 19 patients were classified as having reversible myocardial ischaemia. cTnT levels were significantly higher in patients with reversible myocardial ischaemia on MPI at baseline, at peak exercise and after 1.5 h, but not at 4.5 h post-exercise. In patients with reversible ischaemia on MPI, cTnT levels did not change significantly after exercise stress testing [11.1 (5.2-14.9) ng/l at baseline compared with 10.5 (7.2-16.3) ng/l at 4.5 h post-exercise, P=0.27; values are medians (interquartile range)]. Conversely, cTnT levels increased significantly during testing in patients without reversible myocardial ischaemia [5.4 (3.0-9.0) ng/l at baseline compared with 7.5 (4.6-12.4) ng/l, P<0.001]. In conclusion, baseline cTnT levels are higher in patients with MPI evidence of reversible myocardial ischaemia than those without reversible ischaemia. However, although cTnT levels increase during exercise stress testing in patients without evidence of reversible ischaemia, this response appears to be blunted in patients with evidence of reversible ischaemia. Mechanisms other than reversible myocardial ischaemia may play a role for acute exercise-induced increases in circulating cTnT levels.

Determinants of high-sensitivity cardiac troponin T during acute exacerbation of chronic obstructive pulmonary disease: a prospective cohort study.

BACKGROUND: A high-sensitivity cardiac troponin T (hs-cTnT) concentration above the 99th percentile (i.e. 14 ng/L) is common during Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) and associated with increased mortality. The objective of the study was to identify factors associated with hs-cTnT levels during AECOPD. METHODS: We included 99 patients with AECOPD on admission. As 41 patients had one or more repeat admissions, there were 202 observations in the final analysis. We recorded clinical and biochemical data, medication, spirometry, chest radiographs, and ECGs. The data were analysed for cross-sectional and longitudinal associations using ordinary least square as well as linear mixed models with the natural logarithm of hs-cTnT as the dependent variable. RESULTS: Mean age at inclusion was 71.5 years, mean FEV1/FVC was 45%, and median hs-cTnT was 27.0 ng/L. In a multivariable model there was a 24% increase in hs-cTnT per 10 years increase in age (p < 0.0001), a 6% increase per 10 µmol/L increase in creatinine (p = 0.037), and a 2% increase per month after enrollment (p = 0.046). Similarly, the ratios of hs-cTnT between patients with and without tachycardia (heart rate ≥100/min) and with and without history of arterial hypertension were 1.25 (p = 0.042) and 1.44 (p = 0.034), respectively. We found no significant association between arterial hypoxemia and elevated hs-cTnT. CONCLUSION: Age, arterial hypertension, tachycardia, and serum creatinine are independently associated with the level of hs-cTnT on admission for AECOPD.

Prognostic value of cardiac biomarkers and National Early Warning Score 2 in acute dyspnoea.

OBJECTIVE: Patients hospitalised with acute dyspnoea due to acute heart failure (AHF) have a grave prognosis, but the European Society of Cardiology guidelines recommend no system to risk stratify these patients. The prognostic value of combining National Early Warning Score (NEWS) 2 and established cardiac biomarkers is not known. METHODS: We measured high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and calculated NEWS2 in 314 patients with acute dyspnoea within 24 hours of hospitalisation. Their prognostic merits were assessed in the total cohort and for the subgroup with AHF separately. RESULTS: The median age was 73 (quartile (Q) 1-3, 63-81) years, 48% were women and 143 patients (46%) were hospitalised with AHF. The 114 patients (36%) who died during follow-up (median 823 days, Q1-3, 471-998) had higher concentrations of hs-cTnT (62 vs 33 ng/L, p<0.001) and NT-proBNP (6995 vs 2605 ng/L, p<0.001), and higher NEWS2 (6.1 vs 4.5 points, p<0.001), compared with survivors. Patients with increased vs low NEWS2 clinical risk had higher mortality rates in adjusted analyses in the total cohort (HR 2.11, 95% CI 1.28 to 3.48) and in patients with AHF (HR 2.00, 95% CI 1.54 to 2.60). NEWS2 provided incremental prognostic information compared with biomarkers alone for the total cohort: area under the curve 0.72 vs 0.70, p=0.042, and for the subpopulation with AHF: 0.70 vs 0.67, p=0.014. CONCLUSION: NEWS2 predicts long-term mortality in patients hospitalised due to acute dyspnoea and the subgroup with AHF and provide incremental prognostic information to hs-cTnT and NT-proBNP.

High-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide in acute heart failure: Data from the ACE 2 study.

BACKGROUND: To assess if cardiac troponins can improve diagnostics of acute heart failure (AHF) and provide prognostic information in patients with acute dyspnea. METHODS: We measured cardiac troponin T with a high-sensitivity assay (hs-cTnT) in 314 patients hospitalized with acute dyspnea. The index diagnosis was adjudicated and AHF patients were stratified into AHF with reduced or preserved ejection fraction (HFrEF/HFpEF). The prognostic and diagnostic merit of hs-cTnT was compared to the merit of N-terminal pro-B-type natriuretic peptide (NT-proBNP). RESULTS: In the total population, median age was 73 (quartile [Q] 1-3 63-81) years and 48% were women. One-hundred-forty-three patients were categorized as AHF (46%) and these patients had higher hs-cTnT concentrations than patients with non-AHF-related dyspnea: median 38 (Q1-3 22-75) vs. 13 (4-25) ng/L; p < 0.001. hs-cTnT concentrations were similar between patients with HFrEF and HFpEF (p = 0.80), in contrast to NT-proBNP, which was higher in HFrEF (p < 0.001). C-statistics for discriminating HFpEF from non-AHF-related dyspnea was 0.80 (95% CI 0.73-0.86) for hs-cTnT, 0.79 (0.73-0.86) for NT-proBNP, and 0.83 (0.76-0.89) for hs-cTnT and NT-proBNP in combination. Elevated hs-cTnT remained associated with HFpEF in logistic regression analysis after adjusting for demographics, comorbidities and renal function. During median 27 months of follow-up, 114 (36%) patients died in the total population. Higher hs-cTnT concentrations were associated with increased risk of all-cause mortality after adjustment for clinical variables and NT-proBNP: hazard ratio 1.30 (95% CI 1.07-1.58), p = 0.009. CONCLUSION: hs-cTnT measurements improve diagnostic accuracy for HFpEF and provide independent prognostic information in unselected patients with acute dyspnea.

Superiority of high sensitivity cardiac troponin T vs. I for long-term prognostic value in patients with chest pain; data from the Akershus cardiac Examination (ACE) 3 study.

BACKGROUND: Cardiac troponins (cTn) are essential in the diagnostic assessment of non-ST-segment-elevation acute coronary syndrome (NSTE-ACS). Elevated concentrations of cTnT and cTnI predict cardiovascular events in non-acute settings, but the individual troponin isotype association with long-term mortality in patients with suspected unstable angina pectoris (UAP) is less clear. METHODS: Patients hospitalized with chest pain between June 2009 and December 2010 were included in the Akershus Cardiac Examination 3 Study and followed for median 6.6 (IQR 6.2-7.1) years. The index diagnosis was adjudicated by an independent committee as NSTE-myocardial infarction (NSTEMI), UAP or non-ACS. Blood samples were collected within 24 h of admission and analyzed with high sensitivity assays for cTnT (hs-cTnT, Roche) and cTnI (hs-cTnI, Singulex). RESULTS: Of 402 patients included, 74 (18%) were classified as NSTEMI, 88 (22%) UAP and 240 (60%) non-ACS. hs-cTnI concentrations were detectable in all patients (median 3 [IQR 1-11] ng/L), while hs-cTnT concentrations were above the level of blank in 205 (51%) (median 3 [IQR 3-16] ng/L). In patients with UAP, both log2-transformed hs-cTnT and hs-cTnI were associated with all-cause mortality in analyses that adjusted for other risk factors: HR 2.40 [95% CI 1.75-3.30], p < 0.001 and HR 1.44 [1.14-1.81], p = 0.002. There were no significant sex-dependent differences in the association between hs-cTnT or hs-cTnI and outcome. Time dependent receiver-operating characteristics area under the curve was 0.85 (95% CI 0.79-0.92) for hs-cTnT and 0.74 (0.64-0.84) for hs-cTnI, p = 0.008 for difference between values. CONCLUSIONS: Higher concentrations of hs-cTnT and hs-cTnI were both associated with all-cause mortality in patients with UAP, but the association with outcome was stronger for hs-cTnT than for hs-cTnI.

Diagnostic and prognostic properties of procalcitonin in patients with acute dyspnea: Data from the ACE 2 Study.

BACKGROUND: Procalcitonin (PCT) concentrations increase during bacterial infections and could improve diagnosis of pneumonia and risk stratification in patients with acute dyspnea. METHODS: PCT concentrations were measured <24 h of admission in 310 patients with acute dyspnea and compared to C-reactive protein (CRP) and white blood cells (WBC) in the total cohort and the subset of patients with concomitant acute heart failure (HF). RESULTS: We diagnosed pneumonia in 16 out of 140 patients with acute HF (11%) and in 45 out of 170 patients with non-HF-related dyspnea (27%). PCT concentrations were higher in patients with pneumonia vs. patients without pneumonia, both among acute HF patients (median 2.79 [Q1-3 0.18-5.80] vs. 0.10 [0.07-0.14] ng/mL, p < .001) and non-HF patients (0.22 [Q1-3 0.13-0.77] vs. 0.07 [0.05-0.10] ng/mL, p < .001). CRP and WBC were also higher in patients with pneumonia in both groups, but among acute HF patients, only PCT concentrations were associated with pneumonia in multivariate analysis. In patients with acute HF, receiver-operating statistics area under the curve (ROC-AUC) to diagnose pneumonia was 0.90 (95% CI 0.81-0.98) for PCT, 0.84 (0.73-0.94) for CRP, and 0.72 (0.57-0.87) for WBC. The corresponding ROC-AUCs among patients with non-HF-related dyspnea were 0.88 (0.82-0.93), 0.94 (0.90-0.98), and 0.79 (0.72-0.87), respectively. During a median follow-up of 823 days (Q1-3 471-998) 114 patients died, and PCT and CRP, but not WBC concentrations were associated with all-cause mortality. CONCLUSION: In acute HF patients, PCT concentrations were superior to CRP and WBC to diagnose concurrent pneumonia.

Fibroblast growth factor 23 in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study.

BACKGROUND: Circulating fibroblast growth factor 23 (FGF23) concentrations have been linked to left ventricular remodeling and unfavorable cardiovascular outcomes, but whether FGF23 is associated with heart failure (HF) diagnosis and outcome in unselected patients with dyspnea is unknown. Accordingly, we assessed the diagnostic and prognostic properties of FGF23 in patients presenting to the emergency department with acute dyspnea. METHODS AND RESULTS: FGF23 was measured in 314 patients admitted with acute dyspnea and the diagnostic and prognostic merit was compared to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The diagnosis of acute HF was adjudicated by two independent physicians. Circulating FGF23 concentrations on hospital admission were higher in patients with acute HF vs. patients with non-HF related dyspnea: median 3.60 (IQR 1.24-8.77) vs. 1.00 (0.43-2.20) pmol/L; P<0.001. The receiver-operating statistics area under the curve for acute HF diagnosis was 0.750 (0.699-0.797) for FGF23 and 0.853 (0.809-0.890) for NT-proBNP. Adjusting for clinical risk indices and cardiac biomarkers in multivariate Cox regression analysis, admission FGF23 concentrations were associated with mortality in the total study population (hazard ratio [HR] per 1 SD in lnFGF23 1.74 [1.40-2.16]). FGF23 also reclassified patients into their correct risk strata on top of clinical variables significantly associated with outcomes in the total cohort (net reclassification index 0.386 [0.161-0.612]). In patients with acute HF, both admission FGF23 and NT-proBNP concentrations were associated with mortality. CONCLUSION: Circulating FGF23 concentrations provide incremental prognostic information to established risk indices in patients with acute dyspnea, but do not improve diagnostic accuracy over NT-proBNP measurements.

Mid-regional pro-adrenomedullin in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study.

BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is a surrogate marker for adrenomedullin; a hormone that attenuates myocardial remodeling. Accordingly, we hypothesized that MR-proADM could provide diagnostic and prognostic information in patients with acute dyspnea. METHODS AND RESULTS: We measured MR-proADM by a commercial ELISA on hospital admission in 311 patients with acute dyspnea and compared the utility of MR-proADM with N-terminal pro-B-type natriuretic peptide (NT-proBNP). Blood samples were also available after 24h (n=232) and before discharge (n=94). The principal diagnosis of the index hospitalization was determined by an adjudication committee. MR-proADM concentrations on hospital admission were higher in patients with acute heart failure (HF; n=143) vs. patients hospitalized with non-HF-related dyspnea (n=168): 1.31 (Q1-3 0.97-1.89) vs. 0.85 (0.59-1.15) nmol/L; p<0.001. The receiver-operating characteristics area under the curve (ROC-AUC) for MR-proADM to diagnose HF was 0.77 (95% CI 0.72-0.82) and 0.86 (0.82-0.90) for NT-proBNP. During a median follow-up of 816days, 66/143 patients (46%) with acute HF and 35/84 patients (42%) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) died; p=0.58 between groups. In multivariate Cox regression analyses, admission MR-proADM concentrations were associated with mortality in patients with acute HF (HR 5.90 [3.43-10.13], p<0.001), but not in patients with AECOPD. Admission MR-proADM concentrations also improved risk stratification in acute HF as assessed by the net reclassification index. MR-proADM concentrations decreased from admission to later time points. CONCLUSION: Admission MR-proADM concentrations provide strong prognostic information in patients with acute HF, but modest diagnostic information in patients with acute dyspnea.

Glycosylated Chromogranin A in Heart Failure: Implications for Processing and Cardiomyocyte Calcium Homeostasis.

BACKGROUND: Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function. METHODS AND RESULTS: CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands. Deglycosylation treatment attenuated high molecular weight bands, induced a mobility shift, and increased shorter CgA fragments. Adjusting for established risk indices and biomarkers, circulating CgA levels were found to be associated with mortality in patients with acute HF, but not in patients with acute exacerbation of chronic obstructive pulmonary disease. Low CgA-to-CST conversion was also associated with increased mortality in acute HF, thus, supporting functional relevance of impaired CgA processing in cardiovascular disease. CST was identified as a direct inhibitor of CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, and CST reduced CaMKIIδ-dependent phosphorylation of phospholamban and the ryanodine receptor 2. In line with CaMKIIδ inhibition, CST reduced Ca2+ spark and wave frequency, reduced Ca2+ spark dimensions, increased sarcoplasmic reticulum Ca2+ content, and augmented the magnitude and kinetics of cardiomyocyte Ca2+ transients and contractions. CONCLUSIONS: CgA-to-CST conversion in HF is impaired because of hyperglycosylation, which is associated with clinical outcomes in acute HF. The mechanism for increased mortality may be dysregulated cardiomyocyte Ca2+ handling because of reduced CaMKIIδ inhibition.