Validation of myocarditis diagnoses in the Swedish patient register for analyses of potential adverse reactions to COVID-19 vaccines.

Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain. Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation. Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93-0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation. Conclusion: This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination.

Prognostic importance of biomarkers associated with haemostatic, vascular and endothelial disturbances in acute coronary syndrome patients in relation to kidney function.

BACKGROUND: Patients with kidney failure have a high risk for cardiovascular events. We aimed to evaluate the prognostic importance of selected biomarkers related to haemostasis, endothelial function, and vascular regulation in patients with acute coronary syndrome (ACS), and to study whether this association differed in patients with renal dysfunction. METHODS: Plasma was collected in 1370 ACS patients included between 2008 and 2015. Biomarkers were analysed using a Proximity Extension Assay and a Multiple Reaction Monitoring mass spectrometry assay. To reduce multiplicity, biomarkers correlating with eGFR were selected a priori among 36 plasma biomarkers reflecting endothelial and vascular function, and haemostasis. Adjusted Cox regression were used to study their association with the composite outcome of myocardial infarction, ischemic stroke, heart failure or death. Interaction with eGFR strata above or below 60 ml/min/1.73 m2 was tested. RESULTS: Tissue factor, proteinase-activated receptor, soluble urokinase plasminogen activator surface receptor (suPAR), thrombomodulin, adrenomedullin, renin, and angiotensinogen correlated inversely with eGFR and were selected for the Cox regression. Mean follow-up was 5.2 years during which 428 events occurred. Adrenomedullin, suPAR, and renin were independently associated with the composite outcome. Adrenomedullin showed interaction with eGFR strata (p = 0.010) and was associated with increased risk (HR 1.88; CI 1.44-2.45) only in patients with eGFR ≥60 ml/min/ 1.73 m2. CONCLUSIONS: Adrenomedullin, suPAR, and renin were associated with the composite outcome in all. Adrenomedullin, involved in endothelial protection, showed a significant interaction with renal function and outcome, and was associated with the composite outcome only in patients with preserved kidney function.

Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Cardiac biomarkers retain prognostic significance in patients with heart failure and chronic obstructive pulmonary disease.

AIMS: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2). METHODS: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values. RESULTS: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P < 0.001), but not sST2 (P = 0.165). Over a median 2.0-year follow-up (1.5-2.5), 1717 patients (21%) died, and 1298 (16%) died from cardiovascular causes; 2255 patients (28%) were hospitalized for HF over 1.8 years (0.9-2.1). NT-proBNP, hs-TnT and sST2 predicted the three end points regardless of COPD status. The best cut-offs from receiver-operating characteristics analysis were higher in patients with COPD than in those without. Patients with all three biomarkers higher than or equal to end-point- and COPD-status-specific cut-offs were also those with the worst prognosis. CONCLUSIONS: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status.

Risk-associated management disparities in acute myocardial infarction.

Despite improvements in the treatment of myocardial infarction (MI), risk-associated management disparities may exist. We investigated this issue including temporal trends in a large MI cohort (n = 179,291) registered 2005-2017 in SWEDEHEART. Multivariable models were used to study the associations between risk categories according to the GRACE 2.0 score and coronary procedures (timely reperfusion, invasive assessment ≤ 3 days, in-hospital coronary revascularization), pharmacological treatments (P2Y12-blockers, betablockers, renin-angiotensin-aldosterone-system [RAAS]-inhibitors, statins), structured follow-up and secondary prevention (smoking cessation, physical exercise training). High-risk patients (n = 76,295 [42.6%]) experienced less frequent medical interventions compared to low/intermediate-risk patients apart from betablocker treatment. Overall, intervention rates increased over time with more pronounced increases seen in high-risk patients compared to lower-risk patients for in-hospital coronary revascularization (+ 23.6% vs. + 12.5% in patients < 80 years) and medication with P2Y12-blockers (+ 22.2% vs. + 7.8%). However, less pronounced temporal increases were noted in high-risk patients for medication with RAAS-blockers (+ 8.5% vs. + 13.0%) and structured follow-up (+ 31.6% vs. + 36.3%); pinteraction < 0.001 for all. In conclusion, management of high-risk patients with MI is improving. However, the lower rates of follow-up and of RAAS-inhibitor prescription are a concern. Our data emphasize the need of continuous quality improvement initiatives.

Differences in biomarker concentrations and predictions of long-term outcome in patients with ST-elevation and non-ST-elevation myocardial infarction.

BACKGROUND: Differences in biomarkers reflective of pathobiology and prognosis between ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) are incompletely understood and may offer insights for tailoring of treatment. METHODS: This registry-based study included 538 STEMI and 544 NSTEMI patients admitted 2008-2014. Blood samples were collected day 1-3 after admission and 175 biomarkers were analyzed using Proximity Extension Assay and Multiple Reaction Monitoring mass spectrometry. Adjusted Lasso analysis (penalized logistic regression model) was used to select biomarkers that discriminated STEMI from NSTEMI patients. Biomarkers identified by the Lasso analysis were then evaluated in adjusted Cox regressions for associations with death or major adverse cardiovascular events. RESULTS: Biomarkers strongly discriminated STEMI and NSTEMI when considered simultaneously in adjusted Lasso analysis (c-statistic 0.764). Eleven biomarkers independently discriminated STEMI and NSTEMI; seven showing higher concentrations in STEMI: myoglobin, N-terminal pro-B-type natriuretic peptide, serum amyloid A-1 and A-2 protein, ST2 protein, interleukin-6 and chitinase-3-like protein 1; and four showing higher concentrations in NSTEMI: fibroblast growth factor 23, membrane-bound aminopeptidase P, tumor necrosis factor-related activation-induced cytokine and apolipoprotein C-I. During up to 6.6 years of prognostic follow-up, none of these biomarkers exhibited different associations with adverse outcome between STEMI and NSTEMI. CONCLUSIONS: In the acute setting, biomarkers indicated greater myocardial dysfunction and inflammation in STEMI, whereas they displayed a more diverse pathophysiologic pattern in NSTEMI patients. These biomarkers were similarly prognostic in STEMI and NSTEMI patients. The results do not support treating STEMI and NSTEMI patients differently based on the concentrations of these biomarkers.

Predicting outcome in acute myocardial infarction: an analysis investigating 175 circulating biomarkers.

AIMS: There is a paucity of studies comprehensively comparing the prognostic value of larger arrays of biomarkers indicative of different pathobiological axes in acute myocardial infarction (MI). METHODS AND RESULTS: In this explorative investigation, we simultaneously analysed 175 circulating biomarkers reflecting different inflammatory traits, coagulation activity, endothelial dysfunction, atherogenesis, myocardial dysfunction and damage, apoptosis, kidney function, glucose-, and lipid metabolism. Measurements were performed in samples from 1099 MI patients (SWEDEHEART registry) applying two newer multimarker panels [Proximity Extension Assay (Olink Bioscience), Multiple Reaction Monitoring mass spectrometry]. The prognostic value of biomarkers regarding all-cause mortality, recurrent MI, and heart failure hospitalizations (median follow-up ≤6.6 years) was studied using Lasso analysis, a penalized logistic regression model that considers all biomarkers simultaneously while minimizing the risk for spurious findings. Tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), ovarian cancer-related tumour marker CA 125 (CA-125), and fibroblast growth factor 23 (FGF-23) consistently predicted all-cause mortality in crude and age/sex-adjusted analyses. Growth-differentiation factor 15 (GDF-15) was strongly predictive in the crude model. TRAIL-R2 and B-type natriuretic peptide (BNP) consistently predicted heart failure hospitalizations. No biomarker predicted recurrent MI. The prognostic value of all biomarkers was abrogated following additional adjustment for clinical variables owing to our rigorous statistical approach. CONCLUSION: Apart from biomarkers with established prognostic value (i.e. BNP and to some extent GDF-15), several 'novel' biomarkers (i.e. TRAIL-R2, CA-125, FGF-23) emerged as risk predictors in patients with MI. Our data warrant further investigation regarding the utility of these biomarkers for clinical decision-making in acute MI.

Evaluation of quantitative CMR perfusion imaging by comparison with simultaneous 15O-water-PET.

BACKGROUND: We assessed the quantitative accuracy of cardiac perfusion measurements using dynamic contrast-enhanced MRI with simultaneous 15O-water PET as reference with a fully integrated PET-MR scanner. METHODS: 15 patients underwent simultaneous DCE MRI and 15O-water PET scans at rest and adenosine-stress on an integrated PET-MR scanner. Correlation and agreement between MRI- and PET-based global and regional MBF values were assessed using correlation and Bland-Altman analysis. RESULTS: Three subjects were excluded due to technical problems. Global mean (± SD) MBF values at rest and stress were 0.97 ± 0.27 and 3.19 ± 0.70 mL/g/min for MRI and 1.02 ± 0.28 and 3.13 ± 1.16 mL/g/min for PET (P = 0.66 and P = 0.81). The correlations between global and regional MRI- and PET-based MBF values were strong (r = 0.86 and r = 0.75). The biases were negligible for both global and regional MBF comparisons (0.01 and 0.00 mL/min/g for both), but the limits of agreement were wide for both global and regional MBF, with larger variability for high MBF-values. CONCLUSION: The correlation between simultaneous MBF measurements with DCE MRI and 15O-water PET measured in an integrated PET-MRI was strong but the agreement was only moderate indicating that MRI-based quantitative MBF measurements is not ready for clinical introduction.

Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T.

AIMS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. METHODS AND RESULTS: Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. CONCLUSIONS: Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT.

Revisiting the obesity paradox in heart failure: Per cent body fat as predictor of biomarkers and outcome.

AIMS: Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). METHODS: In an individual patient dataset, BMI was calculated as weight (kg)/height (m) 2 , and PBF through the Jackson-Pollock and Gallagher equations. RESULTS: Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5-2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4-33.0%) with the Jackson-Pollock equation, and 28.0% (23.8-33.5%) with the Gallagher equation, with an extremely strong correlation (r = 0.996, p < 0.001). Patients in the first PBF tertile had the worst prognosis, while patients in the second and third tertile had similar survival. The risks of all-cause and cardiovascular death decreased by up to 36% and 27%, respectively, per each doubling of PBF. Furthermore, prognosis was better in the second or third PBF tertiles than in the first tertile regardless of model variables. Both BMI and PBF were inverse predictors of NT-proBNP, but not hs-TnT. In obese patients (BMI ≥ 30 kg/m2, third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. CONCLUSION: In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.

Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries.

BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD). METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses. RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls. CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts.

Predictors of 10-year changes in levels of N-terminal pro B-type natriuretic peptide and cardiac troponin I in the elderly.

BACKGROUND: Measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) might be useful for monitoring of cardiovascular disease in the elderly. However, it is not clear whether changes in these biomarkers are associated with changes in the cardiovascular risk profile and if this pattern could be modified by changes in lifestyle habits or medications. METHODS: We measured levels of NT-proBNP and cTnI in community-dwelling subjects (PIVUS study) upon visits scheduled at age 70 (n=1007), 75 (n=825) and 80 (n=602). The associations of these biomarkers with repeated measurements of clinical variables (risk factors, lifestyle habits, echocardiographic data and medications) were investigated using sex-adjusted linear mixed random effect models. RESULTS: NT-proBNP and cTnI were positively associated with increasing age. NT-proBNP, but not cTnI, was affected by changes of renal function and the degree of obesity. NT-proBNP was more closely related than cTnI to changes in echocardiographic estimates of cardiac geometry and function. Biomarker levels and/or their changes were inversely associated with a physically more active lifestyle (both NT-proBNP and cTnI) and statin treatment at age 70 (only cTnI). Changes in smoking status or antihypertensive treatment had no effect on biomarker levels. CONCLUSIONS: Changes in NT-proBNP and cTnI levels are associated with different patterns of cardiovascular disease burden when using a longitudinal approach. However, levels of both biomarkers and their changes also reflect changes in the cardiovascular risk profile that might be modifiable. This is an important aspect for the use of any cardiovascular biomarker in an elderly population.

Myocardial Infarction with Nonobstructive Coronary Arteries: The Importance of Achieving Secondary Prevention Targets.

BACKGROUND: Approximately 5% to 10% of all patients with myocardial infarction have nonobstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking. METHODS: In this analysis from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, we investigated 5830 patients with myocardial infarction with nonobstructive coronary arteries (group 1) and 54,637 patients with myocardial infarction with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score-adjusted statistics were used to assess the reduction in the 1-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6 to 10 weeks after the hospitalization and achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, nonsmoking, and participation in exercise training). RESULTS: Patients in group 1 were less often followed up compared with patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6- to 10-week follow-up was associated with a 3% to 20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24%-32% risk reduction) and, to a smaller extent, by participation in exercise training (10%-23% risk reduction). CONCLUSIONS: Selected secondary preventive measures are associated with prognostic benefit in patients with myocardial infarction with nonobstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.

NT-proBNP is a powerful predictor for incident atrial fibrillation - Validation of a multimarker approach.

BACKGROUND: Biomarkers may be of value to identify individuals at risk of developing atrial fibrillation (AF). Using a multimarker approach, this study investigated if the biomarkers; NT-proBNP, high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor-15 (GDF-15), cystatin C and high-sensitivity C-reactive protein (CRP) are independent predictors for incident AF. METHODS: Blood samples were collected from 883 individuals in the Uppsala Longitudinal Study of Adult Men (ULSAM) and 978 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Participants were followed for 10-13years with n=113 incident AF cases in ULSAM and n=148 in PIVUS. The associations between biomarkers and incident AF were analysed in Cox proportional hazards regression models. RESULTS: The hazard ratio (HR) for incident AF was significant for all five biomarkers in unadjusted analyses in both cohorts. Only NT-proBNP remained significant when adjusting for cardiovascular risk factors and the other biomarkers (HR (1SD) 2.05 (1.62-2.59) (ULSAM) and 1.56 (1.30-1.86) (PIVUS), both p<0.001). The C-index improved from 0.64 to 0.69 in ULSAM and from 0.62 to 0.68 in PIVUS, by adding NT-proBNP to cardiovascular risk factors (both p<0.001). The C-index of the CHARGE-AF risk score increased from 0.62 to 0.68 (ULSAM) and 0.60 to 0.66 (PIVUS) by addition of NT-proBNP (p<0.001). CONCLUSIONS: Using a multimarker approach NT-proBNP was the strongest predictor of incident AF in two cohorts, and improved risk prediction when added to traditional risk factors. NT-proBNP significantly improved the predictive ability of the novel CHARGE-AF risk score, although the predictive value remained modest.

GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men.

The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation.

High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.

BACKGROUND: Cardiac troponin is emerging as risk indicator in community-dwelling populations. In this study, we investigated the associations of cardiac troponin T (cTnT) to cardiovascular (CV) disease and outcome in elderly men. METHODS: Cardiac troponin T was measured using a high-sensitive assay in 940 men aged 71 years participating in the Uppsala Longitudinal Study of Adult Men. We assessed both the cross-sectional associations of cTnT to CV risk factors and morbidities including cancer and the longitudinal associations to outcomes over 10 years of follow-up. RESULTS: Cardiac troponin T levels were measurable in 872 subjects (92.8%). In the cross-sectional analyses, cTnT was associated to CV risk factors (diabetes, smoking, and obesity), renal dysfunction, CV disease including atrial fibrillation and coronary artery disease, and biomarkers of inflammation and left ventricular dysfunction. In the longitudinal analyses, cTnT independently predicted total mortality and CV events including stroke. The standardized adjusted hazard ratio regarding the composite CV end point was 1.5 (95% CI 1.3-1.8), P < .001, for men with prevalent CV disease and 1.2 (95% CI 1.0-1.4), P = .02, for men without. Cardiac troponin T improved discrimination metrics for all outcomes in the total population. This was mainly driven by the prognostic value of cTnT in subjects with prevalent CV disease. CONCLUSIONS: In community-dwelling men, cTnT levels are associated to CV risk factors and morbidities and predict both fatal and nonfatal CV events. The relations to outcome are mainly seen in men with prevalent CV disease indicating that the prognostic value of cTnT in subjects free from CV disease is limited.

Associations of mid-regional pro-adrenomedullin levels to cardiovascular and metabolic abnormalities, and mortality in an elderly population from the community.

BACKGROUND: The mid-regional part of the prohormone of adrenomedullin (MR-proADM) is emerging as a novel risk indicator in patients with cardiac disease. We investigated MR-proADM levels and their changes over 5 years in elderly community-dwellers, together with the underlying cardiovascular and metabolic conditions, and the prognostic implications of these measurements. METHODS AND RESULTS: MR-proADM was analyzed using a sandwich immunoassay (Thermo Fisher Scientific) in participants from the PIVUS study. Measurements were performed at 70 (n=1002) and 75 years of age (n=795) together with various measurements of other markers of cardiovascular function. In cross-sectional analyses, MR-proADM was independently related to current smoking, renal dysfunction, obesity, lower left-ventricular ejection fraction, and higher levels of N-terminal pro-B-type natriuretic peptide and C-reactive protein. There were no independent associations to other cardiovascular risk factors or vascular pathologies. MR-proADM levels predicted all-cause mortality during 8.0 years of follow-up independent of cardiovascular risk indicators (adjusted HR 5.1 [95% CI 2.8-9.5]; p<0.001) using results obtained at 70 and 75 years as updated covariates. Baseline MR-proADM levels improved prognostic discrimination (IDI=0.018 [p=0.001]). Also the change in MR-proADM levels over time independently predicted all-cause mortality occurring after 75 years (adjusted HR 13.4 [95% CI 3.5-50.5]; p<0.001). CONCLUSIONS: MR-proADM levels in the elderly integrate information on several relevant aspects in cardiovascular disease, namely cardiovascular risk factors including obesity, low-grade inflammation, renal dysfunction and left-ventricular abnormalities. Furthermore, MR-proADM and its changes over time predicted mortality, and might provide utility as an indicator of the overall cardiovascular risk burden.

Prognostic usefulness of the change in N-terminal pro B-type natriuretic peptide levels to predict mortality in a single community cohort aged ≥ 70 years.

The levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) are closely related to cardiac abnormalities and adverse outcomes in the general population. However, little is known about the course of NT-proBNP levels over time, the underlying conditions, and the prognostic effect of changes. To investigate these issues, we measured the NT-proBNP levels (Elecsys 2010, Roche Diagnostics) in community-dwellers participating in the Prospective Investigation of the Vasculature in Uppsala Seniors study at 70 (n = 1,005) and 75 (n = 817) years of age. The total follow-up was 8.0 years. In subjects with available results from both examinations, the median NT-proBNP levels increased from 106 pg/ml (25th to 75th percentile 62 to 174) to 125 pg/ml (25th to 75th percentile 73-234; p <0.001). The change in NT-proBNP levels was positively and independently related to male gender, baseline information on ischemic electrocardiographic changes, renal dysfunction, impaired left ventricular ejection fraction, and intercurrent cardiovascular events (e.g., myocardial infarction, stroke, or coronary revascularization). The change in NT-proBNP levels independently predicted mortality after the measurements at 75 years of age (all-cause mortality, adjusted hazard ratio 2.4, 95% confidence interval 1.6 to 3.6; cardiovascular mortality, adjusted hazard ratio 2.3, 95% confidence interval 1.2 to 4.5). Compared to those without significant NT-proBNP changes (n = 606), subjects with increasing levels (n = 162) had markedly increased all-cause mortality (adjusted hazard ratio 4.3, 95% confidence interval 2.1 to 8.8). No subject with decreasing NT-proBNP levels (n = 49) died. In conclusion, repeat measurements of NT-proBNP might add useful information to the routine clinical assessment in subjects aged ≥ 70 years, because changes in their levels were associated with cardiovascular risk indicators and strongly predictive of mortality.

Utility of B-type natriuretic peptides and cardiac troponins for population screening regarding cardiac abnormalities.

AIMS: The increasing importance of cardiac disease has generated an interest in improved screening strategies regarding preclinical cardiac abnormalities and employing measurement of circulating biomarkers. This review focuses on the utility of the B-type natriuretic peptides (NP) and the cardiac troponins (cTns) for this purpose. RESULTS: Both the NPs and the cTns are closely related to cardiac structural and functional abnormalities that may progress to symptomatic heart disease, e.g., left ventricular (LV) hypertrophy, LV systolic and diastolic dysfunction. Both biomarkers provide incremental information to each other. However, biomarker results may be confounded by several non-cardiac conditions, and decision thresholds and recommendations on further clinical work-up are as yet not specified. Furthermore, cost issues will probably preclude widespread biomarker screening in general populations. CONCLUSIONS: Measurement of the NPs or cTns is an attractive option for screening for cardiac abnormalities. This may be particularly effective in patients at higher risk for developing overt heart disease. Nevertheless, appropriate diagnostic and therapeutic responses to biomarker results need to be defined before routine screening can be recommended in the community setting.

Improving long-term risk prediction in patients with acute chest pain: the Global Registry of Acute Coronary Events (GRACE) risk score is enhanced by selected nonnecrosis biomarkers.

BACKGROUND: The Global Registry of Acute Coronary Events (GRACE) risk score is widely recommended for risk assessment in patients with acute coronary syndrome. However, there is limited knowledge regarding the utility of this score for long-term risk prediction in unselected patients with acute chest pain and whether it might be improved by the integration of nonnecrosis biomarkers. METHODS: We calculated the GRACE risk score in 453 chest pain patients and assessed its value for risk assessment together with the additive prognostic information obtained from N-terminal pro-B-type natriuretic peptide, C-reactive protein, growth differentiation factor-15 (GDF-15), and cystatin C. RESULTS: After a median follow-up of 5.8 years, 92 patients (20.7%) had died. The GRACE risk score was significantly higher in patients who died (median 146 vs 93, P < .001) and provided a c-statistic regarding mortality of 0.78. A significant increase of the c-statistic was achieved only after addition of GDF-15 (c-statistic 0.81, P = .003) and, to a minor extent, after addition of cystatin C (c-statistic 0.81, P = .035). Assessment of the integrated discriminative improvement yielded similar results. N-terminal pro-B-type natriuretic peptide had only limited incremental prognostic value, and C-reactive protein was not predictive for outcome. CONCLUSION: The GRACE risk score allows for the prediction of mortality in chest pain patients even after almost 6 years of follow-up. However, its predictive value could be further enhanced by the addition of selected nonnecrosis biomarkers, in particular GDF-15 or cystatin C.