Background:Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation.Methods:The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index.Results:The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04–1.34], P=0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6–65.7], P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P<0.001; net reclassification index 1.05, P<0.001; integrated discrimination index 0.20, P<0.001).Conclusions:Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02798731.

中文翻译：

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心脏移植术后冠状动脉微循环障碍和急性细胞排斥反应

背景：急性细胞排斥反应是心脏移植后死亡率和再移植的主要决定因素。我们试图评估通过微循环阻力指数 (IMR) 评估的冠状动脉微循环障碍对心脏移植后急性细胞排斥风险的预后影响。移植后 1 个月的生理评估。IMR是最大充血下的微循环阻力。通过在最大充血情况下使用 3 次室温盐水注射（每次 4 mL）测量充血平均通过时间，IMR 计算为充血远端冠状动脉压力 × 充血平均通过时间。主要终点是移植后 2 年随访期间活检证实的≥2R 级急性细胞排斥反应，并根据 IMR 使用多变量 Cox 比例风险回归进行比较。除了具有临床因素的模型外，IMR 的增量预后价值还通过 C 指数、净重分类指数和综合鉴别指数的比较进行评估。 结果：受者的平均年龄为 51.2±13.1 岁（81.2% 男性)，2年内急性细胞排斥的累积发生率为19.0%。发生急性细胞排斥反应的患者在 1 个月时的 IMR 值显着高于无急性细胞排斥反应的患者（23.1±8.6 vs 16.8±11.1，净重分类指数、综合鉴别指数。结果：受者平均年龄为51.2±13.1岁（男性81.2%），2年急性细胞排斥累积发生率为19.0%。发生急性细胞排斥反应的患者在 1 个月时的 IMR 值显着高于无急性细胞排斥反应的患者（23.1±8.6 vs 16.8±11.1，净重分类指数、综合鉴别指数。结果：受者平均年龄为51.2±13.1岁（男性81.2%），2年急性细胞排斥累积发生率为19.0%。发生急性细胞排斥反应的患者在 1 个月时的 IMR 值显着高于无急性细胞排斥反应的患者（23.1±8.6 vs 16.8±11.1，P = 0.002）。IMR 与急性细胞排斥反应的风险显着相关（每增加 5-U：调整后的风险比，1.18 [95% CI，1.04–1.34]，P = 0.011），预测急性细胞排斥反应的 IMR 的最佳临界值为15. IMR≥15 的患者出现急性细胞排斥反应的风险显着高于 IMR <15 的患者（34.4% 对 3.8%；调整后的风险比，15.3 [95% CI 3.6–65.7]，P <0.001）。将 IMR 添加到临床变量显示出显着更高的急性细胞排斥风险的区分和重新分类能力（C 指数 0.87 对 0.74，P <0.001；净重新分类指数 1.05，P <0.001；综合区分指数 0.20，P<0.001).结论：心脏移植后早期通过 IMR 评估的冠状动脉微循环功能障碍显示与急性细胞排斥的风险显着相关。除了监测心内膜心肌活检外，使用 IMR 进行早期分层可能是一种临床有用的工具，可用于识别心脏移植后未来发生急性细胞排斥反应风险较高的患者。注册：URL：https://www.clinicaltrials.gov；唯一标识符：NCT02798731。