Blood-Based Biomarkers to Search for Atrial Fibrillation in High-Risk Asymptomatic Individuals and Cryptogenic Stroke Patients

Elena Palà; Alejandro Bustamante; Jorge Pagola; Jesus Juega; Jaume Francisco-Pascual; Anna Penalba; Maite Rodriguez; Mercedes De Lera Alfonso; Juan F Arenillas; Juan Antonio Cabezas; Soledad Pérez-Sánchez; Francisco Moniche; Reyes de Torres; Teresa González-Alujas; Josep Lluís Clúa-Espuny; Juan Ballesta-Ors; Domingo Ribas; Juan Acosta; Alonso Pedrote; Felipe Gonzalez-Loyola; Delicia Gentile Lorente; Miguel Ángel Muñoz; Carlos A Molina; Joan Montaner

doi:10.3389/fcvm.2022.908053

Blood-Based Biomarkers to Search for Atrial Fibrillation in High-Risk Asymptomatic Individuals and Cryptogenic Stroke Patients

Front Cardiovasc Med. 2022 Jul 4:9:908053. doi: 10.3389/fcvm.2022.908053. eCollection 2022.

Authors

Elena Palà¹, Alejandro Bustamante^{1

2}, Jorge Pagola³, Jesus Juega³, Jaume Francisco-Pascual^{4

5}, Anna Penalba¹, Maite Rodriguez³, Mercedes De Lera Alfonso⁶, Juan F Arenillas⁶, Juan Antonio Cabezas⁷, Soledad Pérez-Sánchez⁸, Francisco Moniche⁷, Reyes de Torres⁸, Teresa González-Alujas^{5

9}, Josep Lluís Clúa-Espuny^{10

11}, Juan Ballesta-Ors¹¹, Domingo Ribas¹², Juan Acosta¹³, Alonso Pedrote¹³, Felipe Gonzalez-Loyola^{14

15}, Delicia Gentile Lorente^{11

16}, Miguel Ángel Muñoz^{14

15}, Carlos A Molina², Joan Montaner¹

Affiliations

¹ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
² Stroke Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
³ Stroke Unit, Medicine Department, Vall d'Hebrón Hospital and Autonomous University of Barcelona, Barcelona, Spain.
⁴ Arrhythmia Unit-Cardiology Department, Vall d'Hebrón Hospital, Barcelona, Spain.
⁵ Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain.
⁶ Stroke Unit, University Hospital of Valladolid, Valladolid, Spain.
⁷ Stroke Unit, University Hospital Virgen del Rocio, Seville, Spain.
⁸ Stroke Unit, University Hospital Virgen Macarena, Seville, Spain.
⁹ Echocardiography Lab Cardiology Department, Vall d'Hebrón Hospital, Barcelona, Spain.
¹⁰ Equip d'Atenció Primària Tortosa Est, SAP Terres de l'Ebre, Institut Català de la Salut, Tortosa, Spain.
¹¹ Institut d'Investigació en Atenció Primària IDIAP Jordi Gol, Ebrictus Group, Barcelona, Spain.
¹² EAP Sant Pere i Sant Pau, DAP Camp de Tarragona, Institut Català de la Salut, Tarragona, Spain.
¹³ Department of Cardiology, Hospital Universitario Virgen del Rocio, Seville, Spain.
¹⁴ Gerència Atenció Primària de Barcelona, Institut Català de la Salut, Barcelona, Spain.
¹⁵ Institut d'Investigació en Atenció Primària IDIAP Jordi Gol, Unitat Suport Recerca Barcelona, Barcelona, Spain.
¹⁶ Cardiology Department, Hospital Verge de la Cinta, Institut Català de la Salut, Tortosa, Spain.

Abstract

Background: Atrial fibrillation (AF) increases the risk of ischemic stroke in asymptomatic individuals and may be the underlying cause of many cryptogenic strokes. We aimed to test the usefulness of candidate blood-biomarkers related to AF pathophysiology in two prospective cohorts representative of those populations.

Methods: Two hundred seventy-four subjects aged 65-75 years with hypertension and diabetes from the AFRICAT cohort, and 218 cryptogenic stroke patients aged >55 years from the CRYPTO-AF cohort were analyzed. AF was assessed by 4 weeks of monitoring with a wearable Holter device (NuuboTM™). Blood was collected immediately before monitoring started. 10 candidate biomarkers were measured by automated immunoassays (Roche, Penzberg) in the plasma of all patients. Univariate and logistic regression analyses were performed in each cohort separately.

Results: Atrial fibrillation detection rate was 12.4% (AFRICAT cohort) and 22.9% (CRYPTO-AF cohort). 4 biomarkers were significantly increased in asymptomatic individuals with AF [Troponin-T, Angiopoietin-2 (Ang-2), Endocan, and total N-terminal pro-B type natriuretic peptide (NT-proBNP)] and 7 biomarkers showed significantly higher concentrations in cryptogenic stroke patients with AF detection [growth differentiation factor 15, interleukin 6, Troponin-T, Ang-2, Bone morphogenic protein 10, Dickkopf-related protein 3 (DKK-3), and total NT-proBNP]. The models including Ang-2 and total NT-proBNP [AUC 0.764 (0.665-0.863)], and Ang-2 and DKK-3 [AUC = 0.733 (0.654-0.813)], together with age and sex, showed the best performance to detect AF in high-risk asymptomatic individuals, and in cryptogenic stroke patients, respectively.

Conclusion: Blood-biomarkers, in particular, total NT-proBNP, DKK-3, and Ang-2, were associated with AF reflecting two mechanistically different pathways involved in AF pathophysiology (AF stretch and vascular changes). The combination of these biomarkers could be useful in AF screening strategies in the primary care setting and also for searching AF after cryptogenic stroke.

Keywords: atrial fibrillation; biomarkers; cryptogenic stroke; screening; stroke.

Copyright © 2022 Palà, Bustamante, Pagola, Juega, Francisco-Pascual, Penalba, Rodriguez, De Lera Alfonso, Arenillas, Cabezas, Pérez-Sánchez, Moniche, de Torres, González-Alujas, Clúa-Espuny, Ballesta-Ors, Ribas, Acosta, Pedrote, Gonzalez-Loyola, Gentile Lorente, Ángel Muñoz, Molina and Montaner.