なぜ心臓のリズムの問題は早朝に起こりやすいのか(Why heart rhythm problems tend to happen early in the morning)

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2024-04-03 インペリアル・カレッジ・ロンドン(ICL)

朝早くに心臓不整脈が起こりやすい理由が解明されました。インペリアル・カレッジ・ロンドンの研究によると、ストレスホルモンであるコルチゾールの朝の増加が心臓細胞内のイオンチャネルに影響し、心臓のリズムを乱す可能性があることが明らかになりました。これにより、心臓は朝早くにより脆弱になります。これらの発見は新しい治療法の可能性を提供し、朝の心臓リスクを減少させる可能性があります。

<関連情報>

心臓GRが心室性不整脈感受性の日内リズムを媒介する Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility

Roman Tikhomirov,Robert H. Oakley,Cali Anderson,Yirong Xiang,Sami Al Othman,Matthew Smith,Sana Yaar,Eleonora Torre,Jianying Li,Leslie R. Wilson,David R. Goulding,Ian Donaldson,Erika Harno,Luca Soattin,Holly A. Shiels,…
Circulation Research  Published27 Mar 2024
DOI:https://doi.org/10.1161/CIRCRESAHA.123.323464

Abstract

RATIONALE:
Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the early morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood.

OBJECTIVE:
The objectives are to investigate the recruitment of transcription factors to time-of-day differentially accessible chromatin that underpins day-night ion channel rhythms and to assess the significance of this for the heart’s day-night rhythm in VA susceptibility.

METHODS AND RESULTS:
Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the inactive (zeitgeber time, time of lights on, start of sleep period) and active (time of lights off, start of awake period [ZT12]) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) binding site in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts.

CONCLUSIONS:
Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

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