Multiple Biomarkers and Atrial Fibrillation in the General Population

<div><p>Background</p><p>Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF.</p><p>Methods and Results</p><p>In the population-based Gutenberg Health Study (n = 5000), mean age 56±11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9±8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14–3.90; <i>P</i><0.0001), MR-proANP (OR 2.45, 99.5% CI 1.91–3.14; <i>P</i><0.0001), the vascular function marker MR-proADM (OR 1.54, 99.5% CI 1.20–1.99; <i>P</i><0.0001), TnI ultra (OR 1.50, 99.5% CI 1.19–1.90; P<0.0001) and. fibrinogen (OR 1.44, 99.5% CI 1.19–1.75; P<0.0001). Based on a model comprising known clinical risk factors for AF, all biomarkers combined resulted in a net reclassification improvement of 0.665 (99.3% CI 0.441–0.888) and an integrated discrimination improvement of >13%.</p><p>Conclusions</p><p>In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers.</p></div

Multivariable logistic regression models for biomarkers in relation to AF.

<p>*<i>P</i> values were Bonferroni corrected for ten tests. Multivariable-adjustment included age, sex (upper row) and age, sex, body mass index, systolic blood pressure, antihypertensive medication, and a history of cardiovascular disease (lower row). Biomarkers were logarithmically transformed except for glutathione-peroxidase-1 and fibrinogen.</p><p>Abbreviations: AF, atrial fibrillation; CT-pro-endothelin-1, C-terminal pro endothelin-1; TnI ultra, sensitive troponin I ultra; MR-proADM, mid-regional pro adrenomedullin; MR-proANP, midregional pro atrial natriuretic peptide; Nt-proBNP, N-terminal pro B-type natriuretic peptide.</p><p>Multivariable logistic regression models for biomarkers in relation to AF.</p

Regression tree for biomarkers that remained statistically significant in relation to AF in multivariable models.

<p>Provided are the mean that was selected for the split of the tree and the number of individuals for the respective branches of the regression tree. For every branch the classification of individuals according to the model and the correct, clinical diagnosis are shown. In red the number of participants misclassified by the statistical model is indicated. In two individuals the information on AF was missing. Abbreviations: AF, atrial fibrillation; BP, blood pressure; MR-proADM, mid-regional pro adrenomedullin; MR-proANP, midregional pro atrial natriuretic peptide; N-terminal pro B-type natriuretic peptide; TnI, troponin.</p

Characteristics of the sample by AF status.

<p>Provided are mean and standard deviation for continuous variables, or median (25^th/75^th percentile) for variables with a skewed distribution. Number and percent are shown for categorical variables.</p><p>CRP stands for C-reactive protein and PHQ stands for Patient Health Questionnaire.</p

Characteristics of the sample according to AF status.

<p>Provided are mean and standard deviation for continuous variables, or median (25^th and 75^th percentile) for variables with a skewed distribution (|skewness|>1). Number and percent are shown for categorical variables.</p><p>*Sample quantile estimated using parametric model.</p><p>Abbreviations: AF, atrial fibrillation; CT-pro-endothelin-1, C-terminal pro endothelin-1; HDL, high density lipoprotein; MR-proADM, mid-regional pro adrenomedullin; MR-proANP, midregional pro atrial natriuretic peptide; Nt-proBNP, N-terminal pro B-type natriuretic peptide; TnI ultra, sensitive troponin I ultra.</p><p>Characteristics of the sample according to AF status.</p

Violin plots of the distribution of circulating biomarkers in the total sample and in individuals with AF for markers that remained statistically significant in relation to AF in multivariable-adjusted models.

<p>For presentational reasons some outliers were removed from the plots. For MR-proADM values above 2.5 nmol/L (N = 2), Nt-proBNP values above 8000 pg/mL (N = 3), TnI ultra values above 80 pg/mL (N = 12) were excluded. Abbreviations: AF, atrial fibrillation; CT-proET, CT-pro endothelin-1; MR-proADM, mid-regional pro adrenomedullin; MR-proANP, midregional pro atrial natriuretic peptide; N-terminal pro B-type natriuretic peptide; TnI, troponin.</p

Reclassification analysis for biomarkers significantly related to AF in multivariable-adjusted models.

<p>The baseline model comprised Framingham risk score variables <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0112486#pone.0112486-Schnabel3" target="_blank">[21]</a>: age, age², sex, male sex*age², body mass index, systolic blood pressure, antihypertensive medication, congestive heart failure, congestive heart failure*age. All biomarkers except for fibrinogen were logarithmically transformed for analyses. <i>P</i> values were Bonferroni corrected for seven tests.</p><p>R² is Nagelkerke R². Odds ratio, NRI, IDI and AUC are presented with 99.3% confidence interval in brackets.</p><p><b>Abbreviations:</b> AF, atrial fibrillation; AUC, area under the curve; CRP, C-reactive Protein; CT-pro-endothelin-1, C-terminal pro endothelin-1; TnI ultra, sensitive troponin I ultra; IDI, integrated discrimination improvement; MR-proADM, mid-regional pro adrenomedullin; MR-proANP, midregional pro atrial natriuretic peptide; NRI, net reclassification improvement; Nt-proBNP, N-terminal pro B-type natriuretic peptide.</p><p>Reclassification analysis for biomarkers significantly related to AF in multivariable-adjusted models.</p

Depressive symptom dimensions in individuals with AF by inflammatory activity.

<p>Provided are the numbers and percent of individuals or mean±standard deviation or median (25^th/75^th percentile) for skewed variables. The median CRP value was 1.6 mg/L. <i>P</i> values for categorical variables are according to Chi²-test, for continuous variables according to T-test or Mann-Whitney-U test.</p

Multivariable logistic regression of depressive symptom dimensions in relation to AF.

<p>Odds ratios are across categories or for the dichotomous variable as indicated. Atrial fibrillation was used as dependent variable. Multivariable-adjusted models included age, sex (upper row) and age, sex, body mass index, systolic blood pressure, antihypertensive medication, diabetes, current smoking and a family history of myocardial infarction, dyslipidemia (lower row) and respective model R² values.</p

Depressive symptom dimensions in individuals with AF by partnership status.

<p>Provided are the numbers and percent of individuals or mean±standard deviation or median (25^th/75^th percentile) for skewed variables. <i>P</i> values for categorical variables are according to Chi²-test, for continuous variables according toT-test or Mann-Whitney-U test.</p