Circulating biomolecules identify patients with atrial fibrillation at high risk of cardiovascular events

Press release

An analysis of the biomolecule substudy of the EAST – AFNET 4 trial revealed: biomolecule concentrations in the blood of patients with atrial fibrillation can be used to identify patients at high and low cardiovascular risk. Today the findings were presented by Prof. Larissa Fabritz, University Medical Center Hamburg Eppendorf, Hamburg, Germany, at the Frontiers in CardioVascular Biomedicine Congress in Amsterdam and published in Cardiovascular Research (1).

Atrial Fibrillation (AF) is the most common arrhythmia in elderly people. AF often occurs in patients with cardiovascular comorbidities with shared disease mechanisms. Little is known about the disease processes leading to AF-related complications and their interactions in patients with AF.

The EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial demonstrated that early rhythm control – with antiarrhythmic drugs or atrial fibrillation ablation – delivered within one year after AF diagnosis improves outcomes in 2789 patients with early AF and cardiovascular risk factors compared to usual care (UC) over a 5-year follow-up time (2). A series of sub-analyses of the EAST – AFNET 4 data set verified the results for different sub-groups. (3-12).

This substudy tested whether circulating biomolecules can be used to measure AF related disease processes and their interactions in patients and how they relate to stroke, heart failure, acute coronary syndrome, and cardiovcascular death. Paulus Kirchhof, principal investigator of EAST – AFNET 4 and author on the paper, explained: “We were fortunate that we precisely could quantify thirteen biomolecules related to different disease processes in the EAST – AFNET 4 biomolecule study, Clustering methods capturing interactions between biomolecules were applied to identify patients at risk of cardiovascular events based on biomolecule concentrations. Thereby, four AF subphenotypes with distinct biomolecule profiles and risk of complications were identified. The results provide insights into the drivers of AF-related complications in patients.”

The prespecified analysis of the EAST – AFNET4 biomolecule study assigned 1586 patients (71 years old, 46% women) into four clusters based on blood concentrations of thirteen precisely-quantified biomolecules. These biomarkers potentially reflect ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each patient cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow up 2.9 years).

The highest-risk patient cluster mainly showed cardiometabolic disturbances, with elevated concentrations of the biomolecules BMP10, IGFBP7, NT-proBNP, ANGPT2 and GDF15. Patients in the lowest-risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of hsCRP, IL-6, and D-dimer. Patients in the highest-risk cluster had a 5-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control therapy was effective across clusters.

Prof. Fabritz concluded: “The EAST – AFNET 4 biomolecule study showed: Biomolecule concentrations identify cardiometabolic subtypes in patients with atrial fibrillation at high and low cardiovascular risk. Biomolecule-based patient clusters can be used to advance management of atrial fibrillation. Our findings call for future research into the effects of biomolecules on cardiovascular function. These patient clusters open new treatment options in each cluster, enabling research testing the effectiveness in patients with specific subphenotypes.”

The EAST – AFNET 4 biomolecule substudy was performed on an international level in cooperation with the European research consortia CATCH ME and MAESTRIA.



(1) Fabritz L, Chua W, Cardoso VR, Al-Taie C, Borof K, Suling A, Krause L, Kany S, Magnussen C, Wegscheider K, Breithardt G, Crijns HJGM, Camm AJ, Gkoutos G, Ellinor PT, Goette A, Schotten U, Wienhues-Thelen U-H, Zeller T, Schnabel RB, Zapf A, Kirchhof P. Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study. Cardiovasc Res 2024. DOI: 10.1093/cvr/cvae067

(2) Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, Hamann F, Heidbüchel H, Hindricks G, Kautzner J, Kuck K-H, Mont L, Ng GA, Rekosz J, Schön N, Schotten U, Suling A, Taggeselle J, Themistoclakis S, Vettorazzi E, Vardas P, Wegscheider K, Willems S, Crijns HJGM, Breithardt G, for the EAST–AFNET 4 trial investigators. Early rhythm control therapy in patients with atrial fibrillation. N Engl J Med 2020; 383:1305-1316. DOI: 10.1056/NEJMoa2019422

(3) Metzner A, Suling A, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Elvan A, Goette A, Haegeli LM, Heidbuchel H, Kautzner J, Kuck KH, Mont L, Ng GA, Szumowski L, Themistoclakis S, van Gelder IC, Vardas P, Wegscheider K, Willems S, Kirchhof P. Anticoagulation, therapy of concomitant conditions, and early rhythm control therapy: a detailed analysis of treatment patterns in the EAST - AFNET 4 trial. EP Europace 2022; 24:552–564. DOI: 10.1093/europace/euab200

(4) Rillig A, Magnussen C, Ozga, Suling A, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Elvan A, Goette A, Gulizia M, Haegeli LM, Heidbuchel H, Kuck KH, Ng GA, Szumowski L, van Gelder IC, Wegscheider K, Kirchhof P. Early rhythm control therapy in patients with heart failure. Circulation 2021;144(11):845-858. DOI: 10.1161/CIRCULATIONAHA.121.056323

(5) Willems S, Borof K, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Gessler N, Goette A, Haegeli LM, Heidbuchel H, Kautzner J, Ng GA, Schnabel R, Suling A, Szumowski L, Themistoclakis S, Vardas P, van Gelder IC, Wegscheider K, Kirchhof P. Systematic, early rhythm control therapy equally improves outcomes in asymptomatic and symptomatic patients with atrial fibrillation: the EAST-AFNET 4 Trial. Eur Heart J. 2022; 43:1219-1230. DOI: 10.1093/eurheartj/ehab593.

(6) Goette a, Borof K, Breithardt G, Camm AJ, Crijns H, Kuck KH, Wegscheider K, Kirchhof P, MD. Presenting Pattern of Atrial Fibrillation and Outcomes of Early Rhythm Control Therapy. J Am Coll Cardiol. 2022; 80:283-95. DOI: 10.1016/j.jacc.2022.04.058

(7) Rillig A, Borof K, Breithardt G, Camm AJ, Crijns HJGM, Goette A, Kuck KH, Metzner A, Vardas P, Vettorazzi E, Wegscheider K, Zapf A, Kirchhof P. Early rhythm control in patients with atrial fibrillation and high comorbidity burden. Circulation. 2022 Sep 13;146(11):836-847. DOI: 10.1161/CIRCULATIONAHA.122.060274

(8) Jensen M, Suling A, Metzner A, Schnabel R, Borof K, Goette A, Haeusler KG, Zapf A, Wegscheider K, Fabritz L, Diener H-C, Thomalla G, Kirchhof P. Early rhythm-control therapy for atrial fibrillation in patients with a history of stroke: a subgroup analysis of the EAST- AFNET 4 trial. Lancet Neurol 2023; 22: 45–54. DOI: 10.1016/PIIS1474-4422(22)00436-7 

(9) Eckardt L, Sehner S, Suling A, Borof K, Breithardt G, Crijns HJGM, Goette A, Wegscheider K, Zapf A, Camm AJ, Metzner A, Kirchhof P. Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST – AFNET 4 trial. Eur Heart J, 2022 Oct 21;43(40):4127-4144. DOI: 10.1093/eurheartj/ehac471

(10) Van Gelder IC, Ekrami NK, Borof K, Fetsch T, Magnussen C, Mulder BA, Schnabel R, Wegscheider K, Rienstra M, Kirchhof P; EAST-AFNET 4 Trial Investigators. Sex Differences in Early Rhythm Control of Atrial Fibrillation in the EAST-AFNET 4 Trial. J Am Coll Cardiol. 2023 Feb 28;81(8):845-847. DOI: 10.1016/j.jacc.2022.12.011.

(11) Gottschalk S, Kany S, König H-H, Crijns HJGM, Vardas P, Camm AJ, Wegscheider K, Metzner A, Rillig A, Kirchhof P, Dams J. Cost- effectiveness of early rhythm-control versus usual care in atrial fibrillation care: an analysis based on the German subsample of the EAST-AFNET 4 trial. EP Europace 2023 May 19;25(5). DOI: 10.1093/europace/euad051

(12) Kany S, Al-Taie C, Roselli C, Pirruccello JP, Borof K, Reinbold C, Suling A, Krause L, Reissmann B, Schnabel R, Zeller T, Zapf A, Wegscheider K, Fabritz L, Ellinor PT, Kirchhof P. Association of genetic risk and outcomes in patients with early rhythm control therapy in atrial fibrillation: results from the EAST-AFNET4 study. Cardiovasc Res 2023 Aug 7;119(9):1799-1810. DOI: 10.1093/cvr/cvad027


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Funding: AFNET, BMBF, DZHK, EHRA, Deutsche Herzstiftung, Abbott, Sanofi


About the EAST – AFNET 4 trial

EAST – AFNET 4 is an investigator-initiated trial (IIT) that compared two different treatment strategies in atrial fibrillation. The EAST – AFNET 4 trial tested whether an early, comprehensive rhythm control therapy can prevent adverse cardiovascular outcomes in patients with atrial fibrillation (AF) compared to usual care.

A total of 2789 patients with early AF (diagnosed less than a year ago) and at least two cardiovascular conditions (approximating a CHA₂DS₂-VASc score >=2) were enrolled by 135 sites in 11 countries during 2011 to 2016. Patients were randomized 1:1 to early rhythm control therapy or usual care, stratified by sites. Patients in both groups received guideline-recommended treatment for underlying cardiovascular conditions, anticoagulation, and rate control.

All patients in the early rhythm control group received antiarrhythmic drugs or catheter ablation after randomization (chosen by the local study teams). Rhythm control therapy was escalated with AF ablation and/or antiarrhythmic drugs when recurrent AF was documented clinically or by ECG, including monitoring with patient-operated ECG devices.

Patients in the usual care group were initially managed with rate control. Rhythm control therapy was only used to improve atrial fibrillation-related symptoms despite optimal rate control, following current guidelines.


About the Atrial Fibrillation NETwork (AFNET)

The Atrial Fibrillation NETwork is an interdisciplinary research network comprising scientists and physicians from hospitals and practices dedicated to improving the management of atrial fibrillation through coordinated research in Germany, Europe, and worldwide. Its main objective is to conduct high quality investigator-initiated clinical trials and registries on a national and international level as well as translational research projects. The AFNET continues the long-term activities of the network which has been funded by the German Federal Ministry of Research and Education over a decade. Since January 2015, specific projects and infrastructures of the AFNET are funded by the German Centre for Cardiovascular Research (DZHK), and some projects by EU research grants. AFNET has long expertise in the management of atrial fibrillation, but also provides support for work in other fields informing cardiovascular care. The results of 20 years of clinical and translational research improved the lives of patients with cardiovascular diseases and influenced treatment guidelines.