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AIMS

Acute cellular rejection (ACR) following heart transplantation (HTX) is associated with long-term graft loss and increased mortality. Disturbed mitochondrial bioenergetics have been identified as pathophysiological drivers in heart failure, but their role in ACR remains unclear. We aimed to prove functional disturbances of myocardial bioenergetics in human heart transplant recipients with mild ACR by assessing myocardial mitochondrial respiration using high-resolution respirometry, digital image analysis of myocardial inflammatory cell infiltration, and clinical assessment of HTX patients. We hypothesized that (i) mild ACR is associated with impaired myocardial mitochondrial respiration and (ii) myocardial inflammation, systemic oxidative stress, and myocardial oedema relate to impaired mitochondrial respiration and myocardial dysfunction.

METHODS AND RESULTS

We classified 35 HTX recipients undergoing endomyocardial biopsy according International Society for Heart and Lung Transplantation criteria to have no (0R) or mild (1R) ACR. Additionally, we quantified immune cell infiltration by immunohistochemistry and digital image analysis. We analysed mitochondrial substrate utilization in myocardial fibres by high-resolution respirometry and performed cardiovascular magnetic resonance (CMR). ACR (1R) was diagnosed in 12 patients (34%), while the remaining 23 patients revealed no signs of ACR (0R). Underlying cardiomyopathies (dilated cardiomyopathy 50% vs. 65%; P = 0.77), comorbidities (type 2 diabetes mellitus: 50% vs. 35%, P = 0.57; chronic kidney disease stage 5: 8% vs. 9%, P > 0.99; arterial hypertension: 59% vs. 30%, P = 0.35), medications (tacrolimus: 100% vs. 91%, P = 0.54; mycophenolate mofetil: 92% vs. 91%, P > 0.99; prednisolone: 92% vs. 96%, P > 0.99) and time post-transplantation (21.5 ± 26.0 months vs. 29.4 ± 26.4 months, P = 0.40) were similar between groups. Mitochondrial respiration was reduced by 40% in ACR (1R) compared with ACR (0R) (77.8 ± 23.0 vs. 128.0 ± 33.0; P < 0.0001). Quantitative assessment of myocardial CD3 -lymphocyte infiltration identified ACR (1R) with a cut-off of >14 CD3 -lymphocytes/mm (100% sensitivity, 82% specificity; P < 0.0001). Myocardial CD3 infiltration (r = -0.41, P < 0.05), systemic oxidative stress (thiobarbituric acid reactive substances; r = -0.42, P < 0.01) and myocardial oedema depicted by global CMR derived T2 time (r = -0.62, P < 0.01) correlated with lower oxidative capacity and overt cardiac dysfunction (global longitudinal strain; r = -0.63, P < 0.01).

CONCLUSIONS

Mild ACR with inflammatory cell infiltration associates with impaired mitochondrial bioenergetics in cardiomyocytes. Our findings may help to identify novel checkpoints in cardiac immune metabolism as potential therapeutic targets in post-transplant care.

AIMS

METHODS AND RESULTS

CONCLUSIONS

目的

心脏移植（HTX）后急性细胞排斥（ACR）与长期移植物丢失和死亡率增加有关。线粒体生物能量障碍已被确定为心力衰竭的病理生理驱动因素，但它们在 ACR 中的作用仍不清楚。我们旨在通过使用高分辨率呼吸测定法评估心肌线粒体呼吸、心肌炎症细胞浸润的数字图像分析以及 HTX 患者的临床评估，证明轻度 ACR 患者存在心肌生物能量障碍的功能障碍。我们假设（i）轻度 ACR 与心肌线粒体呼吸受损有关，（ii）心肌炎症、全身氧化应激和心肌水肿与线粒体呼吸受损和心肌功能障碍有关。

方法和结果

我们根据国际心肺移植协会的标准，对 35 名接受心内膜活检的 HTX 受者进行分类，分为无（0R）或轻度（1R）ACR。此外，我们通过免疫组织化学和数字图像分析定量评估免疫细胞浸润。我们通过高分辨率呼吸测定法分析心肌纤维中的线粒体底物利用情况，并进行心血管磁共振（CMR）检查。诊断 12 名患者（34%）存在 ACR（1R），而其余 23 名患者无 ACR 迹象（0R）。基础心肌病（扩张型心肌病：50% vs. 65%；P=0.77）、合并症（2 型糖尿病：50% vs. 35%，P=0.57；慢性肾脏病 5 期：8% vs. 9%，P>0.99；动脉高血压：59% vs. 30%，P=0.35）、药物（他克莫司：100% vs. 91%，P=0.54；霉酚酸酯：92% vs. 91%，P>0.99；泼尼松龙：92% vs. 96%，P>0.99）和移植后时间（21.5±26.0 个月 vs. 29.4±26.4 个月，P=0.40）在两组之间相似。与 ACR（0R）相比，ACR（1R）的线粒体呼吸降低了 40%（77.8±23.0 比 128.0±33.0；P<0.0001）。定量评估心肌 CD3-淋巴细胞浸润发现，>14 个 CD3-淋巴细胞/mm 时可识别 ACR（1R）（100%灵敏度，82%特异性；P<0.0001）。心肌 CD3 浸润（r=-0.41，P<0.05）、全身氧化应激（硫代巴比妥酸反应物质；r=-0.42，P<0.01）和 CMR 衍生的 T2 时间显示的心肌水肿（r=-0.62，P<0.01）与较低的氧化能力和明显的心脏功能障碍（整体纵向应变；r=-0.63，P<0.01）相关。