Role of NLRP3 Inflammasome in Heart Failure Patients Undergoing Cardiac Surgery as a Potential Determinant of Postoperative Atrial Fibrillation and Remodeling: Is SGLT2 Cotransporter Inhibition an Alternative for Cardioprotection?

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Antioxidants Pub Date : 2024-11-14 DOI:10.3390/antiox13111388
Rodrigo L Castillo, Jorge Farías, Cristian Sandoval, Alejandro González-Candia, Esteban Figueroa, Mauricio Quezada, Gonzalo Cruz, Paola Llanos, Gonzalo Jorquera, Sawa Kostin, Rodrigo Carrasco
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Abstract

In heart failure (HF) patients undergoing cardiac surgery, an increased activity of mechanisms related to cardiac remodeling may determine a higher risk of postoperative atrial fibrillation (POAF). Given that atrial fibrillation (AF) has a negative impact on the course and management of HF, including the need for anticoagulation therapy, identifying the factors associated with AF occurrence after cardiac surgery is crucial for the prognosis of these patients. POAF is thought to occur when various clinical and biochemical triggers act on susceptible cardiac tissue (first hit), with oxidative stress and inflammation during cardiopulmonary bypass (CPB) surgery being potential contributing factors (second hit). However, the molecular mechanisms involved in these processes remain poorly characterized. Recent research has shown that patients who later develop POAF often have pre-existing abnormalities in calcium handling and activation of NLRP3-inflammasome signaling in their atrial cardiomyocytes. These molecular changes may make cardiomyocytes more susceptible to spontaneous Ca2+-releases and subsequent arrhythmias, particularly when exposed to inflammatory mediators. Additionally, some clinical studies have linked POAF with elevated preoperative inflammatory markers, but there is a need for further research in order to better understand the impact of CPB surgery on local and systemic inflammation. This knowledge would make it possible to determine whether patients susceptible to POAF have pre-existing inflammatory conditions or cellular electrophysiological factors that make them more prone to developing AF and cardiac remodeling. In this context, the NLRP3 inflammasome, expressed in cardiomyocytes and cardiac fibroblasts, has been identified as playing a key role in the development of HF and AF, making patients with pre-existing HF with reduced ejection fraction (HFrEF) the focus of several clinical studies with interventions that act at this level. On the other hand, HFpEF has been linked to metabolic and non-ischemic risk factors, but more research is needed to better characterize the myocardial remodeling events associated with HFpEF. Therefore, since ventricular remodeling may differ between HFrEF and HFpEF, it is necessary to perform studies in both groups of patients due to their pathophysiological variations. Clinical evidence has shown that pharmacological therapies that are effective for HFrEF may not provide the same anti-remodeling benefits in HFpEF patients, particularly compared to traditional adrenergic and renin-angiotensin-aldosterone system inhibitors. On the other hand, there is growing interest in medications with pleiotropic or antioxidant/anti-inflammatory effects, such as sodium-glucose cotransporter 2 inhibitors (SGLT-2is). These drugs may offer anti-remodeling effects in both HFrEF and HFpEF by inhibiting pro-inflammatory, pro-oxidant, and NLRP3 signaling pathways and their mediators. The anti-inflammatory, antioxidant, and anti-remodeling effects of SGLT-2 i have progressively expanded from HFrEF and HFpEF to other forms of cardiac remodeling. However, these advances in research have not yet encompassed POAF despite its associations with inflammation, oxidative stress, and remodeling. Currently, the direct or indirect effects of NLRP3-dependent pathway inhibition on the occurrence of POAF have not been clinically assessed. However, given that NLRP3 pathway inhibition may also indirectly affect other pathways, such as inhibition of NF-kappaB or inhibition of matrix synthesis, which are strongly linked to POAF and cardiac remodeling, it is reasonable to hypothesize that this type of intervention could play a role in preventing these events.

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接受心脏手术的心衰患者体内 NLRP3 炎症小体的作用是术后心房颤动和重塑的潜在决定因素:SGLT2 共转运体抑制是心脏保护的替代疗法吗?
在接受心脏手术的心力衰竭(HF)患者中,与心脏重塑相关的机制活动增加可能决定了术后心房颤动(POAF)的风险较高。鉴于心房颤动(AF)对心房颤动的病程和治疗(包括抗凝治疗的需要)有负面影响,确定与心脏手术后发生心房颤动相关的因素对这些患者的预后至关重要。POAF 被认为是在各种临床和生化诱因作用于易感心脏组织时发生的(第一击),心肺旁路(CPB)手术过程中的氧化应激和炎症是潜在的诱因(第二击)。然而,这些过程所涉及的分子机制仍鲜为人知。最近的研究表明,后来发展成 POAF 的患者往往在心房心肌细胞中预先存在钙处理异常和 NLRP3-炎症信号转导激活。这些分子变化可能会使心肌细胞更容易发生自发性 Ca2+ 释放和随后的心律失常,尤其是在暴露于炎症介质时。此外,一些临床研究已将 POAF 与术前炎症指标升高联系起来,但仍需进一步研究,以更好地了解 CPB 手术对局部和全身炎症的影响。有了这方面的知识,就有可能确定易患 POAF 的患者是否已存在炎症或细胞电生理因素,从而使其更容易发展为房颤和心脏重塑。在这种情况下,在心肌细胞和心脏成纤维细胞中表达的 NLRP3 炎性体已被确认在高房颤和心房颤动的发展过程中起着关键作用,这使得射血分数降低的原发性高房颤(HFrEF)患者成为几项临床研究的重点,这些研究在这一层面采取了干预措施。另一方面,射血分数降低性心房颤动(HFpEF)与代谢和非缺血性风险因素有关,但要更好地描述与 HFpEF 相关的心肌重塑事件还需要更多的研究。因此,由于 HFrEF 和 HFpEF 的心室重塑可能有所不同,因此有必要对这两类患者进行病理生理学研究。临床证据显示,对 HFrEF 有效的药物疗法可能无法为 HFpEF 患者带来同样的抗重塑疗效,尤其是与传统的肾上腺素能和肾素-血管紧张素-醛固酮系统抑制剂相比。另一方面,人们对具有多效应或抗氧化/抗炎作用的药物越来越感兴趣,如钠-葡萄糖共转运体 2 抑制剂(SGLT-2is)。这些药物可通过抑制促炎、促氧化和 NLRP3 信号通路及其介质,对 HFrEF 和 HFpEF 起到抗重塑作用。SGLT-2 i 的抗炎、抗氧化和抗重塑作用已从 HFrEF 和 HFpEF 逐步扩展到其他形式的心脏重塑。然而,尽管 POAF 与炎症、氧化应激和重塑有关,但这些研究进展尚未涵盖 POAF。目前,临床上尚未评估 NLRP3 依赖性通路抑制对 POAF 发生的直接或间接影响。不过,鉴于 NLRP3 通路抑制也可能间接影响其他通路,如抑制 NF-kappaB 或抑制基质合成,而这些通路与 POAF 和心脏重塑密切相关,因此有理由假设这类干预措施可在预防这些事件中发挥作用。
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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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