ExperimentalIncrement of late sodium currents in the left atrial myocytes and its potential contribution to increased susceptibility of atrial fibrillation in castrated male mice
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice and represents a major cause of morbidity and mortality. Testosterone deficiency seems to be a causal factor for the increased propensity for AF. The risk of AF incidence increases with increment in age, which is accompanied by a decline in testosterone.1 In patients with lone AF, the levels of testosterone were lower than those of normal controls.2 Moreover, a recent study showed that testosterone is associated with the incidence of AF in a cohort of men. In men older than 80 years, testosterone deficiency is strongly associated with AF risk.3
The causal effect of testosterone deficiency on AF has also been verified in animal studies. Tsuneda et al4 showed that castration of male rats increased atrial arrhythmogenicity of Langendorff-perfused hearts that was abolished by administration of testosterone. The increased AF susceptibility of castrated rats was attributed to up-regulation of the ryanodine receptor type 2 and the sodium–calcium exchanger.4 In another study, Tsai et al5 evaluated the effects of androgen receptor knockout (ARKO) on atrial electrophysiology and arrhythmogenesis. They found that the left atria of ARKO mice had a lower negative resting membrane potential and a >90% action potential duration (APD) than wild-type control by conventional microelectrode technique, with the findings explained by reduced expression of Kir2.1, Kir3.1, and Kv7.1. To date, the functional alteration of ion channels and its contribution to AF susceptibility on testosterone deficiency remain unclear.
The late component of sodium current (INa-L) is a depolarizing current that has been shown to participate in the development of AF.6, 7 Activation of INa-L increases atrial APD.8 In a cardiac hypertrophy model of rabbits, higher density of INa-L was recorded in the left atrial myocytes, accompanied by the occurrence of early afterdepolarizations (EADs) and spontaneous automaticity (SA). Blockade of INa-L abolished all atrial EADs and SA.7 Sossalla et al found that INa-L was significantly increased in isolated atrial myocytes from AF patients than in those with sinus rhythm.6 Administration of the selective INa-L blockers ranolazine, eleclazine, and GS967 dramatically inhibited the occurrence of atrial arrhythmias.6, 9, 10 However, the role of INa-L in the testosterone deficiency–related AF remains unclear. In the current study, we explored the susceptibility of AF in a mouse model of testosterone deprivation by castration in vivo and the alteration of INa-L in isolated left atrial myocytes. The therapeutic effects of testosterone replacement and INa-L blocking on AF in castrated mice were also evaluated.
Section snippets
Animals
Male ICR mice were purchased from the Animal Center of the Second Affiliated Hospital of Harbin Medical University (Harbin, China). Mice were kept under standard animal room conditions (temperature 21° ± 1°C, humidity 55%–60%) with food and water ad libitum. All animal studies were approved by the Institutional Animal Care and Use Committee of Harbin Medical University, People's Republic of China. All animal care and experimental procedures were in accordance with the regulations of the
Serum DHT levels in mice
We first examined the levels of serum DHT in normal, castrated, and castrated with DHT replacement mice. In castrated mice, the content of DHT dropped dramatically (P <.05 vs normal) and only trace amounts of DHT were detected. Replacement of DHT restored the physiologic concentration of DHT (Figure 1).
AF susceptibility in castrated mice and effects of DHT replacement
We then evaluated the inducibility of AF in castrated mice. The induction rate of AF increased from 20% in normal mice to 75% in castrated mice (P <.05 vs normal). Administration of DHT reduced
Discussion
In this study, we discovered that up-regulation of INa-L led to APD prolongation and increased susceptibility to AF in castrated mice, which were alleviated by administration of DHT. Moreover, we confirmed the therapeutic effect of blocking INa-L by ranolazine on AF occurrence in castrated mice.
Previous studies have established the association between testosterone deficiency and AF.2, 3 However, to the best of our knowledge, only 1 experimental study provided direct evidence for the causal role
Conclusion
Our study findings demonstrate that testosterone deprivation induced the increase of INa-L, which led to APD prolongation and increased AF susceptibility. Testosterone supplementation or INa-L inhibition represents a potential strategy for treatment of AF in elderly male patients with testosterone deficiency.
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2019, European Journal of PharmacologyCitation Excerpt :INaL inhibitor ranolazine has been shown to possess anti-arrhythmic effects and improve atrial diastolic function in human atrium (Sossalla et al., 2010). Our previous study had found that application of INaL inhibitor ranolazine, eleclazine and GS967 inhibits the occurrence of atrial fibrillation in castrated mice (Zhang et al., 2017). It has been suggested that selective inhibition of INaL by GS967 affords antiarrhythmic effects by suppressing DADs-induced triggered activities (Sicouri et al., 2013).
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2018, Canadian Journal of CardiologyCitation Excerpt :Androgen-receptor knockout mice show APD prolongation and decreased resting membrane potential, related to reduced expression of inward-rectifier K+ channels.119 In another study, INaL was enhanced in castrated mice, and INaL inhibitors prevented AF.120 These studies point to an afterdepolarization-promoting effect of decreasing testosterone activity with aging; however, further work is needed to clarify the precise role in AF, as well as the contribution of other hormonal changes.
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This work was supported by the Funds for Creative Research Groups of The National Natural Science Foundation of China (81421063); National Natural Science Foundation of China (81130088 to Dr. B.-F. Yang and 81470463 to Dr. Z.-W. Pan); Program for New Century Excellent Talents in University (to Dr. Z-W. Pan); and Yu Weihan Excellent Youth Foundation of Harbin Medical University (001000004 to Dr. Z.-W. Pan). Dr. Y. Zhang and H.-M. Wang contributed equally to this work.