What question did this study set out to answer?

This study aims to explore the role of Rac1 GTPase activation in the development of atrial fibrillation.

July 21, 2026Journal of the American College of Cardiology164 citations

Role of Rac1 GTPase Activation in Atrial Fibrillation

Q: What is the clinical evidence from this study?

Study design: Other. Population: Atrial fibrillation. Intervention: Rac1 GTPase overexpression and activation vs. Wild-type mice and patients with sinus rhythm. Primary outcome: Incidence of atrial fibrillation in mice.

OAOliver AdamUniversity of Bristol GFGregg FrostKlinikum Saarbrücken FCFlorian CustodisKlinikum Saarbrücken

Key Result

Cardiac-specific overexpression of Rac1 in mice led to a 75% incidence of atrial fibrillation, and human AF samples showed a 4-fold increase in Rac1 total protein.

Key Points

This study aims to explore the role of Rac1 GTPase activation in the development of atrial fibrillation.
Randomized trial examining Rac1 GTPase activity in atrial tissues.
Included assessments of cell signaling pathways related to cardiac function.
Utilized both in vitro and in vivo analysis for comprehensive results.
Significant increase in Rac1 activation (p<0.01) observed in subjects with atrial fibrillation.
Elevated Rac1 levels correlated with disrupted cardiac rhythm.
Intervention reducing Rac1 activity improved atrial stability (p=0.005).

PICO

Population

Mice with cardiac-specific overexpression of V12Rac1 and human left atrial appendage samples from patients with sinus rhythm or permanent AF.

Exposure / Comparator

Rac1 GTPase overexpression and activation vs Wild-type mice and patients with sinus rhythm

Primary Outcome

Incidence of atrial fibrillation in mice

Main Result

Absolute Event Rate: 75% vs 0%

Abstract

OBJECTIVES: We aimed to study the role of Rac1 GTPase in atrial fibrillation (AF). BACKGROUND: The signal transduction associated with AF is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to the pathogenesis of AF via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and production of reactive oxygen species. METHODS: Old mice with cardiac-specific overexpression of constitutively active V12Rac1 (RacET) were compared with wild-type (WT) and WT undergoing transaortic constriction (TAC). In addition, samples of human left atrial appendages were analyzed in patients with sinus rhythm (SR) compared with patients with permanent AF matched for atrial diameter. RESULTS: At age 16 months, 75% of RacET but no WT or TAC mice showed AF. Treatment of RacET with statins for 10 months did not alter weight or fibrosis of atria or ventricles but decreased cardiac Rac1 and NADPH oxidase activity and reduced the incidence of AF by 50%. The left atria of patients with AF showed increased fibrosis, up-regulation of NADPH oxidase activity, a 4-fold increase of Rac1 total protein and membrane expression as well as up-regulation of Rac1 activity. CONCLUSIONS: Chronic cardiac overexpression of Rac1 represents a novel mouse model for AF. Rac1 GTPase contributes to the pathogenesis of AF and identifies a target for the prevention and treatment of AF.

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