Abstract
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.
Highlights
Acute myocardial infarction (AMI) patients are prone to a variety of arrhythmias, among which ventricular arrhythmia has a higher incidence, and it is one of the important factors leading to sudden death and endangering the lives of patients
The elevation in MI serum does not necessarily mean that the fibroblast growth factor 21 (FGF21) concentration is increased in the interstitial space within the heart; the results in Figure 1C showed that the level of FGF21 in heart tissue homogenate was significantly increased in the acute MI phase, which began to decrease in chronic MI period, relative to acute MI phase
IK1-mediated potassium ion balance is the main component of the resting membrane potential (RMP) and we found that FGF21 can significantly restore the 4-phase RMP of AC16 cardiomyocytes, so in this study, we mainly tested the effect of FGF21 on the IK1 current
Summary
Acute myocardial infarction (AMI) patients are prone to a variety of arrhythmias, among which ventricular arrhythmia has a higher incidence, and it is one of the important factors leading to sudden death and endangering the lives of patients. Human fibroblast growth factors (FGFs) are heparin-binding proteins that contain 23 members which can be divided into seven subfamilies based on phylogeny and sequence, which makes up a cytokine superfamily that regulates a plethora of developmental processes, including regulating mitosis, differentiation, development, metabolism, and angiogenic therapeutic applications (Beenken and Mohammadi, 2009; Itoh et al, 2016b) These functions are mediated, in part, by the interaction of FGFs with relatively high-affinity cell-surface receptors, microRNAs (miRNAs), and subsequent alterations in gene expression within responsive cells. Our previous study uncovered for the first time that FGF21 treatment markedly reduced arrhythmia susceptibility of infarcted hearts in mice by suppressing miR-143 expression and mediating the EGR1SCN5A/KCNJ2 pathway in MI mice (Li et al, 2020) It remains unclear whether FGF21 has preventive effects on ischemic arrhythmias in humans. Our results unraveled for the first time that FGF21 protects NaV1.5 and Kir2.1 channels by receptors against arrhythmias after MI in humans
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