Colitis induced ventricular alternans increases the risk for ventricular arrhythmia

IF 4.9 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Carlos H. Pereira , Hiroki Kittaka , Edward J. Ouille V , Jonathas F.Q. Almeida , Andrès F. Pélaez , Ali Keshavarzian , Lothar A. Blatter , Kathrin Banach
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Abstract

Inflammatory bowel disease was linked to an increased risk for conduction defects and ventricular arrhythmia. It coincides with dysregulation of gut microbiota, increased inflammation, and deregulation of the renin-angiotensin system. In this study, we aimed to determine the mechanism of colitis-induced electrophysiological remodeling that increases the risk for ventricular arrhythmia.
In a mouse model of dextran sulfate sodium induced active colitis (3.5 %, 7 days) cardiac electrophysiological properties were quantified during active inflammation. Electrocardiographic recordings exhibited a prolonged QT duration in mice with active colitis compared to control. Field potential (FP) recordings of Langendorff perfused colitis-hearts exhibited increased FP dispersion, a reduced threshold for ventricular alternans, and an increased propensity for spatially discordant alternans. The increased propensity for alternans was also reflected in isolated ventricular myocytes where Ca2+ transient alternans occurred at lower pacing frequencies and increased alternans ratios. The action potential was unchanged during colitis but myocytes exhibited a prolonged Ca2+ transient duration that corresponded with attenuated phospholamban phosphorylation. Stimulating cellular SERCA activity (Istaroxime), normalized the propensity for alternans. Serum levels of Angiotensin II (AngII) were increased during colitis and Angiotensin-converting enzyme (ACE) inhibitor or AngII receptor type 1 blocker prevented the increased alternans inducibility in isolated myocytes and hearts.
Our data demonstrate that active colitis promotes reversible remodeling of ventricular Ca2+ handling properties and increases the propensity for alternans and arrythmia. The changes can be prevented by ACE or AT1R inhibition supporting a cardiac benefit for controlling RAS signaling in patients with active colitis.
结肠炎引起的心室交替增加室性心律失常的风险。
炎症性肠病与传导缺陷和室性心律失常的风险增加有关。它与肠道微生物群失调、炎症增加和肾素-血管紧张素系统失调相吻合。在这项研究中,我们旨在确定结肠炎诱导的电生理重构增加室性心律失常风险的机制。在右旋糖酐硫酸钠诱导的小鼠活动性结肠炎模型中(3.5 %,7 天),在活动性炎症期间对心脏电生理特性进行量化。与对照组相比,心电图记录显示活动性结肠炎小鼠QT间期延长。Langendorff灌注结肠炎心脏的场电位(FP)记录显示FP弥散增加,心室交替阈值降低,空间不一致交替倾向增加。交替倾向的增加也反映在分离的心室肌细胞中,Ca2+短暂交替发生在较低的起搏频率和增加的交替比率。结肠炎期间的动作电位没有变化,但肌细胞表现出延长的Ca2+短暂持续时间,这与磷蛋白磷酸化的减弱相对应。刺激细胞SERCA活性(司他肟),使替代倾向正常化。血清血管紧张素II (AngII)水平在结肠炎期间升高,血管紧张素转换酶(ACE)抑制剂或AngII受体1型阻滞剂可阻止离体心肌细胞和心脏诱导性升高。我们的数据表明,活动性结肠炎促进心室Ca2+处理特性的可逆重塑,并增加了交替和心律失常的倾向。这种变化可以通过ACE或AT1R抑制来预防,支持对活动性结肠炎患者控制RAS信号的心脏益处。
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来源期刊
CiteScore
10.70
自引率
0.00%
发文量
171
审稿时长
42 days
期刊介绍: The Journal of Molecular and Cellular Cardiology publishes work advancing knowledge of the mechanisms responsible for both normal and diseased cardiovascular function. To this end papers are published in all relevant areas. These include (but are not limited to): structural biology; genetics; proteomics; morphology; stem cells; molecular biology; metabolism; biophysics; bioengineering; computational modeling and systems analysis; electrophysiology; pharmacology and physiology. Papers are encouraged with both basic and translational approaches. The journal is directed not only to basic scientists but also to clinical cardiologists who wish to follow the rapidly advancing frontiers of basic knowledge of the heart and circulation.
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