BACKGROUND
Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia
worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically,
endurance exercise. Most conditions linked to AF are associated with elevated atrial
pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis,
and inflammation. We previously established adverse atrial changes and arrhythmogenesis
required the pro-inflammatory and mechanosensitive cytokine tumor necrosis factor
(TNF) in intense swim exercised mice. Thus, we hypothesize that stretch-mediated TNF-dependent
signaling may provide a unifying mechanism linking AF in exercise and disease.
METHODS AND RESULTS
We developed a clinically-relevant mouse model of aortic regurgitation (AR), which
is characterized by diastolic volume overload and elevated left ventricular end-diastolic
(LVEDPs) and atrial pressures, to study atrial stretch-dependent TNF-mediated AF pathogenesis.
AR was induced by retrograde puncture of the aortic valve in 8-week-old CD1 wild-type
and whole-body TNF knockout (TNF-/-) mice. Four weeks after regurgitation, AR resulted
in volume overload-mediated progressive LV dilatation, functional impairment, hypertrophy,
and elevated LVEDPs in the absence of ventricular arrhythmia inducibility in both
groups. In wild-type mice, AR resulted in adverse atrial remodeling, characterized
by atrial hypertrophy and fibrosis, decreased conduction velocity, reduced atrial
effective refractory period and action potential duration, and increased in vivo and
ex vivo AF susceptibility. By contrast, TNF-/- prevented AR-induced adverse atrial
remodeling and arrhythmia inducibility, independent of ventricular changes.
CONCLUSION
Our results establish that adverse atrial remodeling and AF vulnerability with AR
requires TNF, providing a mechanistic link between elevated atrial pressures, adverse
remodeling, and AF susceptibility with CV disease and exercise.
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© 2021 Published by Elsevier Inc.
