Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering
myocardial ischemia. Liver-derived
fibroblast growth factor 21 (
FGF21) is an endocrine regulator, which exerts metabolic actions by favoring
glucose and
lipids metabolism. Emerging evidence has shown a beneficial effect of
FGF21 on
cardiovascular diseases, but the role of
FGF21 on ventricular arrhythmias following
myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of
FGF21 on cardiomyocytes after MI in humans. Patients with
arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7-10 after the onset of MI for measuring
FGF21 levels using ELISA. Here, we found that the serum level of
FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7-10, relative to the Control samples. In order to clarify the regulation of
FGF21 on
arrhythmia, two kinds of
arrhythmia animal models were established in this study, including ischemic
arrhythmia model (MI rat model) and nonischemic
arrhythmia model (
ouabain-induced guinea pig
arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with
normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by
FGF21 compared to the rhbFGF21-untreated group in the
ouabain model. Consistently, in vitro study also demonstrated that
FGF21 administration was able to shorten action potential duration (APD) in
hydrogen peroxide-treated AC16 cells. Mechanically,
FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac
sodium current (I Na) and inward rectifier
potassium (I k1) in AC16 cells induced by
hydrogen peroxide. Moreover, the restorative effect of
FGF21 on NaV1.5 and Kir2.1 was eliminated when
FGF receptors were inhibited. Collectively,
FGF21 has the potential role of ameliorating transmembrane
ion channels remodeling through the NaV1.5/Kir2.1 pathway by
FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic
therapy in clinics.