Ncardia Services B.V, J.H. Oortweg 21, 2333 CH, Leiden, The Netherlands.
Dept. of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
Stem Cell Res Ther. 2024 Sep 4;15(1):280. doi: 10.1186/s13287-024-03814-0.
Atrial fibrillation has an estimated prevalence of 1.5-2%, making it the most common cardiac arrhythmia. The processes that cause and sustain the disease are still not completely understood. An association between atrial fibrillation and systemic, as well as local, inflammatory processes has been reported. However, the exact mechanisms underlying this association have not been established. While it is understood that inflammatory macrophages can influence cardiac electrophysiology, a direct, causative relationship to atrial fibrillation has not been described. This study investigated the pro-arrhythmic effects of activated M1 macrophages on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes, to propose a mechanistic link between inflammation and atrial fibrillation.
Two hiPSC lines from healthy individuals were differentiated to atrial cardiomyocytes and M1 macrophages and integrated in an isogenic, pacing-free, atrial fibrillation-like coculture model. Electrophysiology characteristics of cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity using multi electrode arrays. Cocultures were additionally treated using glucocorticoids to suppress M1 inflammation. Bulk RNA sequencing was performed on coculture-isolated atrial cardiomyocytes and compared to meta-analyses of atrial fibrillation patient transcriptomes.
Multi electrode array recordings revealed M1 to cause irregular beating and reduced electrogram amplitude. Conduction analysis further showed significantly lowered conduction homogeneity in M1 cocultures. Transcriptome sequencing revealed reduced expression of key cardiac genes such as SCN5A, KCNA5, ATP1A1, and GJA5 in the atrial cardiomyocytes. Meta-analysis of atrial fibrillation patient transcriptomes showed high correlation to the in vitro model. Treatment of the coculture with glucocorticoids showed reversal of phenotypes, including reduced beat irregularity, improved conduction, and reversed RNA expression profiles.
This study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in atrial cardiomyocytes cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using glucocorticoids. Overall, these results point at macrophage-mediated inflammation as a potential AF induction mechanism and offer new targets for therapeutic development. The findings strongly support the relevance of the proposed hiPSC-derived coculture model and present it as a first of its kind disease model.
心房颤动的患病率估计为 1.5-2%，是最常见的心律失常。导致和维持这种疾病的过程仍不完全清楚。已经报道了心房颤动与全身和局部炎症过程之间的关联。然而，这种关联的确切机制尚未建立。虽然已经了解到炎症巨噬细胞可以影响心脏电生理学，但尚未描述与心房颤动的直接因果关系。本研究调查了激活的 M1 巨噬细胞对人诱导多能干细胞（hiPSC）衍生的心房肌细胞的致心律失常作用，以提出炎症与心房颤动之间的机制联系。
从健康个体中分离出两条 hiPSC 系，并分化为心房肌细胞和 M1 巨噬细胞，并整合到无起搏的、类似心房颤动的共培养模型中。使用多电极阵列分析共培养物的电生理特征，以分析心率不规则性、电图幅度和传导速度。共培养物还使用糖皮质激素处理，以抑制 M1 炎症。对共培养分离的心房肌细胞进行 bulk RNA 测序，并与心房颤动患者转录组的荟萃分析进行比较。
多电极阵列记录显示 M1 导致不规则搏动和电图幅度降低。传导分析进一步显示 M1 共培养物的传导均匀性显著降低。转录组测序显示关键心脏基因如 SCN5A、KCNA5、ATP1A1 和 GJA5 的表达减少。心房颤动患者转录组的荟萃分析显示与体外模型高度相关。共培养物用糖皮质激素处理显示表型逆转，包括不规则搏动减少、传导改善和 RNA 表达谱逆转。
本研究建立了 M1 激活与随后发生的心房心律失常之间的因果关系，这在与激活的巨噬细胞共培养的心房肌细胞中自发电激活的不规则性中得到证实。进一步，使用糖皮质激素可以缓解心率不规则性。总的来说，这些结果表明巨噬细胞介导的炎症可能是心房颤动的一种潜在诱导机制，并为治疗开发提供了新的靶点。研究结果强烈支持所提出的 hiPSC 衍生共培养模型的相关性，并将其作为首例疾病模型。
