@article {9539, title = {A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study).}, journal = {Europace}, volume = {25}, year = {2023}, month = {2023 Nov 02}, abstract = {

AIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study.

METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83\%) were novel and 29 (38\%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points.

CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.

}, keywords = {Atrial Fibrillation, Biomarkers, Endosomal Sorting Complexes Required for Transport, Humans, Natriuretic Peptide, Brain, Oxidoreductases Acting on Sulfur Group Donors, Peptide Fragments, Prognosis, Prospective Studies, Proteomics, Risk Factors}, issn = {1532-2092}, doi = {10.1093/europace/euad320}, author = {Jonmundsson, Thorarinn and Steindorsdottir, Anna E and Austin, Thomas R and Frick, Elisabet A and Axelsson, Gisli T and Launer, Lenore and Psaty, Bruce M and Loureiro, Joseph and Orth, Anthony P and Aspelund, Thor and Emilsson, Valur and Floyd, James S and Jennings, Lori and Gudnason, Vilmundur and Gudmundsdottir, Valborg} } @article {9536, title = {Proteomic prediction of incident heart failure and its main subtypes.}, journal = {Eur J Heart Fail}, year = {2023}, month = {2023 Nov 08}, abstract = {

AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.

METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with nonparametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on NT-proBNP and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study (CHS).

CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to eight years, with predictor performance significantly improving for events occurring less than one year ahead, a finding replicated in an external cohort study. This article is protected by copyright. All rights reserved.

}, issn = {1879-0844}, doi = {10.1002/ejhf.3086}, author = {Emilsson, Valur and Jonsson, Brynjolfur G and Austin, Thomas R and Gudmundsdottir, Valborg and Axelsson, Gisli T and Frick, Elisabet A and Jonmundsson, Thorarinn and Steindorsdottir, Anna E and Loureiro, Joseph and Brody, Jennifer A and Aspelund, Thor and Launer, Lenore J and Thorgeirsson, Gudmundur and Kortekaas, Kirsten A and Lindeman, Jan H and Orth, Anthony P and Lamb, John R and Psaty, Bruce M and Kizer, Jorge R and Jennings, Lori L and Gudnason, Vilmundur} }