Vascular Senescense and Endothelial Function　― Can We Apply It to Atrial Fibrillation? ―

In this issue of the Journal, Pan et al¹ report on collecting peripheral blood mononuclear cells from 131 participants, including 26 healthy individuals and 105 symptomatic paroxysmal atrial fibrillation (PAF) patients (54.1±10.8 years old) who underwent catheter ablation therapy. They found that PAF patients had a shorter leukocyte telomere length (LTL) than healthy individuals, but that there was no significant difference in LTL between PAF patients and normal subjects aged ≥50 years. However, healthy individuals <50 years of age (n=17) had longer LTLs than PAF patients (n=31). Within the PAF group, patients aged ≤50 years did not have significantly longer LTLs than those >50 years old, but LTL correlated positively with left atrial (LA) voltage and negatively with biatrial scar area.

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These findings are interesting, even though we know that >90% of patients with AF are older than 65 years and that the frequency of AF increases with age.² Pan et al’s study suggests that PAF itself may affect LTL and their results showed a positive correlation between LTL and LA voltage and a negative correlation with biatrial scar area, which suggests not only an effect on cardiac function by PAF but also an effect of LTL and/or PAF on organic change. The authors should pay attention to the LTL of young patients with AF at the point when catheter ablation is indicated.

Senescence refers to a level of cellular aging that is divided into 2 categories: replicative senescence and stress-induced senescence (SIS).^3,4 SIS is usually not accompanied by LTL shortening. LTL shortening is, therefore, a characteristic phenomenon of replicative senescence. The authors provide a characterization of young AF patients, and in future, expect to study the relationships between LTL and factors related to the course of infectious diseases, including severity, duration, and differences in treatment between patients younger and older than 50 years. These issues appear to be very important.

As mentioned above, during replicative senescence, there is an increase in senescence-associated (SA)-β-gal (a senescence marker) activity in the lysosome, and shortening of TL is usually accompanied by inactivation of telomerase (hTERT) in cells such as leukocytes.⁵ In a previous study by my group of endothelial cells, the effect was mostly associated with reduced reactive oxygen species and increased endothelial nitric oxide synthase activity.⁶ A series of siRNA experiments indicated that prevention of endothelial cell senescence may act as a brake on endothelial cellular senescence.⁷ In the current review, we may apply the characteristics of endothelial cell senescence to senescence in peripheral mononuclear cells. In other words, replicative senescence occurs in peripheral mononuclear cells in AF patients (Figure). It might be important to specify whether the cellular components of the cardiac stimulation conduction system in AF patients undergo replicative senescence.⁸

Figure.

In physiological aging or under high glucose stimuli, replicative senescence accompanying shortening of telomere length, inactivation of telomerase etc. occurs. This type of senescence is related to endothelial dysfunction and progression of atherosclerosis. On the other hand, simple oxidative stress and subculture in vitro are classified as stress-induced senescence, which usually does not accompany a change in telomere length. In atrial fibrillation, such phenomena may occur. NO, nitric oxide.

There are several studies of the relationship between shortening of TL and the occurrence and/or severity of diseases such as stroke, myocardial infarction, and type 2 diabetes mellitus.^2–5 These diseases are accompanied by apoptosis/necrosis of affected cells, and the relationship to telomere shortening is easily understood. In this sense, the relationship of telomere shortening to AF may mean that AF is a sign of a severe life-threatening disease. Taken together, the presented data show that additional mechanisms may exist, such as regulation of cellular senescence; therefore, interest in studying these is increasing. Further large-scale follow-up study is desired.

References

• 1.   Pan KL, Hsiao YW, Lin YJ, Lo LW, Hu YF, Chung FP, et al. Shorter leukocyte telomere length is associated with atrial remodeling and predicts recurrence in younger patients with paroxysmal atrial fibrillation after radiofrequency ablation. Circ J 2019; 83: 1449–1455.
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• 5.   Hayashi T, Kotani H, Yamaguchi T, Taguchi K, Iida M, Ina K, et al. Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes. Proc Natl Acad Sci USA 2014; 111: 1168–1173.
• 6.   Hayashi T, Matsui-Hirai H, Miyazaki-Akita A, Fukatsu A, Funami J, Ding QF, et al. Endothelial cellular senescence is inhibited by nitric oxide: Implications in atherosclerosis associated with menopause and diabetes. Proc Natl Acad Sci USA 2006; 103: 17018–17023.
• 7.   Tsuboi T, Maeda M, Hayashi T. Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence. PLoS One 2018; 13: e0192252.
• 8.   Haycock PC, Heydon EE, Kaptoge S, Butterworth AS, Thompson A, Willeit P. Leucocyte telomere length and risk of cardiovascular disease: Systematic review and meta-analysis. BMJ 2014; 349: g4227–g4231.