Association of genetic risk and outcomes in patients with atrial fibrillation

TY - JOUR

T1 - Association of genetic risk and outcomes in patients with atrial fibrillation

T2 - interactions with early rhythm control in the EAST-AFNET4 trial

AU - Kany, Shinwan

AU - Al-Taie, Christoph

AU - Roselli, Carolina

AU - Pirruccello, James P

AU - Borof, Katrin

AU - Reinbold, Carla

AU - Suling, Anna

AU - Krause, Linda

AU - Reissmann, Bruno

AU - Schnabel, Renate B

AU - Zeller, Tanja

AU - Zapf, Antonia

AU - Wegscheider, Karl

AU - Fabritz, Larissa

AU - Ellinor, Patrick T

AU - Kirchhof, Paulus

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2023/8/7

Y1 - 2023/8/7

N2 - AIMS: The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known.METHODS AND RESULTS: Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001].CONCLUSIONS: Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment.REGISTRATION: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

AB - AIMS: The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known.METHODS AND RESULTS: Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001].CONCLUSIONS: Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment.REGISTRATION: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

U2 - 10.1093/cvr/cvad027

DO - 10.1093/cvr/cvad027

M3 - SCORING: Journal article

C2 - 37264683

VL - 119

SP - 1799

EP - 1810

JO - CARDIOVASC RES

JF - CARDIOVASC RES

SN - 0008-6363

IS - 9

ER -