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Aim Cardiovascular disease (CVD) is a leading cause of death in both men and women. Type 1 and 2 diabetes mellitus (DM1 and DM2) are well-known risk factors for CVD. In addition, gestational diabetes mellitus (GDM) is a female sex-specific risk factor for CVD. Here, we measure circulating concentrations of cardiac troponin T (cTNT), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) during pregnancy—a window of time often referred to as a cardiovascular stress test for women. Methods This study utilized data from 384 pregnant women: 64 with DM1, 16 with DM2, 35 with GDM and 269 euglycemic controls. Blood was predominantly sampled within a week before delivery. Cardiovascular biomarker concentrations were measured in serum using electrochemiluminescence immunoassay. Result Circulating cTnT levels were higher in women with DM1, DM2 and GDM as compared to controls, whereas NT-proBNP and GDF-15 levels were only increased in women with DM1. Glucose dysregulation, assessed by third trimester HbA1c levels, positively correlated with all three CVD biomarker levels, whereas pregestational body mass index correlated negatively with GDF-15. Conclusions Our results support the presence of myocardial affection in women with diabetic disorders during pregnancy. Although pregestational DM1 in this study was associated with the most adverse CVD biomarker profile, women with GDM displayed an adverse cTnT profile similar to what we found in women with pregestational DM2. This supports that women with GDM should be offered long-term intensified cardiovascular follow-up and lifestyle advice following delivery, similarly to the well-established CV follow-up of women with pregestational DM.

Supplemental Digital Content is available in the text., Background: Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown. Methods: Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers. Results: Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P

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 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.

Cardiovascular disease (CVD) is the leading cause of death in women, yet sex-specific risk factors remain understudied. Preeclampsia and other adverse pregnancy outcomes imply an increased maternal cardiovascular risk. We hypothesized that cardiac troponin T (cTnT), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) are increased in such pregnancies and correlate with markers of placental dysfunction. We also investigated these cardiovascular biomarkers 1 or 3 years postpartum. Prior to delivery, we included serum from 417 pregnant women: 55 early-onset preeclampsia (EO-PE), 63 late-onset preeclampsia (LO-PE), 30 gestational hypertension (GH) and 269 healthy controls. Postpartum, we included 341 women 1 or 3 years after delivery: 26 EO-PE, 107 LO-PE, 61 GH, and 147 healthy pregnancies. Prior to delivery, median cTnT and NT-proBNP concentrations were higher in women with EO-PE, LO-PE, or GH than in controls. Median GDF-15 was higher in EO-PE and LO-PE compared to controls. Postpartum, GDF-15 was elevated in women with previous EO-PE. Markers of placental dysfunction correlated with CVD biomarkers in pregnancy, but not postpartum. Our findings underscore the cardiovascular burden of hypertensive disorders of pregnancy and the crosstalk with placental function. The upregulation of circulating GDF-15 following early-onset preeclampsia is in line with the epidemiological excessive risk of premature CVD in this group of women. GDF-15 may be explored for targeting postpartum women with most to gain from intensified preventive follow-up for CVD.

ObjectivePatients 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.MethodsWe 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.ResultsThe 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, pConclusionNEWS2 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.

Background Diabetes mellitus (DM) is associated with increased risk of left ventricular (LV) remodeling and incident heart failure. However, the associations between dysglycemia and subclinical cardiac disease in middle-aged subjects recruited from the general population are not established. Purpose To assess the associations of dysglycemia and diagnostic DM thresholds with indices of subclinical cardiac injury and dysfunction in the general population. Methods We included participants born in 1950 from the Akershus Cardiac Examination 1950 Study with available biomarker measurements (n=3,688). We used regression models and restricted cubic splines (knots selected from lowest Akaike Information Criterion) to assess the association between glycated hemoglobin A1c (HbA1c) and cardiac troponin T (cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and echocardiographic parameters. We classified participants with self-reported diagnosis of DM or HbA1c ≥6.5% (48 mmol/L) as DM, participants with HbA1c 5.7–6.5% as pre-DM, and participants with HbA1c Results Mean age was 63.9±0.7 years, mean body mass index (BMI) 27.2±4.4 kg/m2, and 1,795 participants (49%) were women. DM was classified in 380 participants (10%), pre-DM in 1,630 participants (44%) and no-DM in 1,678 participants (46%). Increasing HbA1c concentrations were associated with younger age, male sex, obesity, hypercholesterolemia, hypertension, and established coronary artery disease in adjusted analyses. In models adjusted for age, sex, BMI, smoking, hypertension, atrial fibrillation, coronary artery disease and renal function, greater HbA1c was associated with increasing logcTnT and logCRP concentrations, decreasing logNT-proBNP concentrations and worse global longitudinal strain and E/e' (p Conclusion We found robust, linear associations between HbA1c and indices of subclinical cardiac injury and dysfunction among participants classified as pre-DM, while associations were more attenuated among participants with DM. Preventive measures for cardiovascular disease should be considered also in patients with dysglycemia and HbA1c below the established cutoff for DM. Figure 1. P-values for overall trend Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Akserhus University Hospital

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.

Procalcitonin (PCT) concentrations increase during bacterial infections and could improve diagnosis of pneumonia and risk stratification in patients with acute dyspnea.PCT concentrations were measured24 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).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.In acute HF patients, PCT concentrations were superior to CRP and WBC to diagnose concurrent pneumonia.

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.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.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 (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.

BACKGROUNDThe 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.METHODSWe 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.RESULTSIn 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.CONCLUSIONSNT-proBNP concentrations were higher, and diagnostic and prognostic accuracy was improved, by pretreating tubes with deglycosylation enzymes.

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.

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.

Objectives To assess the merit of a novel single-epitope sandwich (SES) assay specific to the stable part of BNP in patients with reversible myocardial ischemia as post-translational modifications of BNP may influence assay performance. Design and methods We measured BNP concentration by a conventional assay and the SES-BNP assay in 198 patients referred for myocardial perfusion imaging (MPI). BNP concentration was determined before and immediately after exercise stress testing, and 1.5 and 4.5 h later. Patients were categorized according to MPI results. Results BNP concentration was higher with both assays at all time points in patients with reversible myocardial ischemia ( n = 19) compared to the other patients ( n = 179). Measuring BNP after stress testing or calculating the changes in BNP concentration did not improve diagnostic accuracy compared to baseline measurements: SES-BNP: AUC 0.71 (95% CI 0.58–0.84) vs. conventional BNP: 0.71 (0.59–0.83), p = 0.96. By linear regression analysis, reversible myocardial ischemia was significantly associated with baseline SES-BNP concentration ( p = 0.043), but not with measurements by the conventional assay ( p = 0.089). In multivariate logistic regression models, only baseline measurement with the SES-BNP assay was significantly associated with reversible myocardial ischemia: odds ratio [logarithmical transformed BNP] 2.00 (95% CI 1.16–3.47), p = 0.013. The SES-BNP assay, but not the conventional BNP assay, reclassified a significant proportion of the patients towards their correct category on top of the best clinical model of our data set: NRI = 0.47, p = 0.04. Conclusions The SES-BNP assay was significantly associated with reversible myocardial ischemia as assessed by several statistical indices, while a conventional BNP assay was not.

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

Reduced arterial vasodilatatory capacity is a marker of coronary heart disease. The aim was to investigate if the difference between the vasodilatory response before and after exercise, as assessed by non-invasive methodology, is related to endothelial and inflammatory biomarkers.Post-ischemic hyperemia after 5 min of arterial occlusion was examined before and after a bicycle test with strain-gauge plethysmography (measuring peak reactive hyperemia in the forearm) and peripheral arterial tonometry (PAT hyperemia ratio: measuring pulse waves in the index finger relative to the contra-lateral index finger) in 30 healthy males. A low PAT hyperemia ratio or a low peak reactive hyperemia reflects endothelial dysfunction. Inflammatory and endothelial biomarkers were assessed.A low peak reactive hyperemia and a low PAT hyperemia ratio before the bicycle test was associated with a high percentage increase in peak reactive hyperemia after exercise (r = - 0.68, p0.001; r = - 0.35, p = 0.06, respectively). Asymmetric dimethylarginine and interleukin-10 were associated with the percentage increase in peak reactive hyperemia in multiple linear regression analyses (β: 165 (confidence interval [CI], 34-296), p = 0.02; β: 19 (CI, - 0.5-39), p = 0.06, respectively).The difference in the vasodilatory response before and after exercise, as assessed by non-invasive methodology, is related to endothelial and inflammatory biomarkers in healthy males.

Udgivelsesdato: 2010-Aug BACKGROUND: Circulating levels of osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is predictive of death and hospitalization for heart failure after acute coronary syndrome. The association between OPG and outcome in patients with chronic heart failure (CHF) is unknown. METHODS: Plasma OPG levels at baseline were assessed in 1,229 patients with CHF recruited from 51 clinical centers and included in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF) trial. Patients were randomized to n-3 polyunsaturated fatty acids (1 g/d) or rosuvastatin (10 mg/d) versus placebo. Osteoprotegerin was analyzed by enzyme-linked immunosorbent assay. The association between OPG and outcome was assessed by Cox proportional hazards regression models. RESULTS: During a median follow-up time of 3.9 years, 332 patients died; and 791 patients died or were hospitalized because of cardiovascular causes. By univariate analysis, baseline OPG levels were strongly associated with the incidence of death (hazard ratio {HR} [95% CI] 1.53 [1.40-1.67] per 1-SD increase in log OPG). After adjustment for conventional risk markers, OPG remained a significant predictor of death (HR [95% CI] 1.20 [1.06-1.35], P < .001). Similar findings were observed for the composite end point (HR [95% CI] 1.34 [1.07-1.69], P = .012). CONCLUSION: In patients with CHF, OPG is associated with the incidence of death independently of conventional cardiovascular risk factors.