Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).
Kidney Transplant Department (A.L., O.A.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France.
Circulation. 2020 Jun 16;141(24):1954-1967. doi: 10.1161/CIRCULATIONAHA.119.044924. Epub 2020 May 4.
Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development.
Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality.
A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age (<0.001), donor male sex (<0.001), donor tobacco consumption (=0.001), recipient dyslipidemia (=0.009), class II anti-human leukocyte antigen donor-specific antibodies (=0.004), and acute cellular rejection ≥2R (=0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality (<0.001).
In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.
心脏移植后发生的冠状动脉血管病（CAV）是导致心脏移植受者死亡的主要原因。目前对于人群水平上 CAV 轨迹的原型知之甚少。我们旨在确定 CAV 的不同进化特征，并确定免疫和非免疫因素在 CAV 发展中的各自作用。
心脏移植受者来自 4 个学术中心（巴黎的皮提-萨尔佩特里埃医院和乔治·蓬皮杜医院、鲁汶天主教大学和洛杉矶的雪松西奈医学中心；2004-2016 年）。患者接受了前瞻性、基于方案的监测，包括重复进行冠状动脉造影术以及对临床、组织学和免疫参数进行系统评估。主要结局是预测 CAV 轨迹。我们通过使用无监督潜在类别混合模型来确定 CAV 轨迹。然后，我们确定了 CAV 轨迹的独立预测变量及其与死亡率的关系。
共纳入 1301 例患者（欧洲队列 815 例，美国队列 486 例）。移植后中位随访时间为 6.6 年（四分位距，4-9.1 年），共分析了 4710 次冠状动脉造影术。我们在 10 年内确定了 4 种不同的 CAV 轨迹特征。这 4 种轨迹的特征分别为：（1）1 年内无 CAV，且随时间推移无进展（56.3%）；（2）1 年内无 CAV，但迟发性缓慢 CAV 进展（7.6%）；（3）1 年内有轻度 CAV，且随时间推移轻度进展（23.1%）；（4）1 年内有轻度 CAV，且进展加速（13.0%）。该模型显示出良好的区分度（0.92）。在评估的候选预测因素中，确定了这 4 种轨迹的 6 个早期独立预测因素：供者年龄（<0.001）、供者男性（<0.001）、供者吸烟（=0.001）、受者血脂异常（=0.009）、Ⅱ类抗人白细胞抗原供者特异性抗体（=0.004）和急性细胞性排斥反应≥2R（=0.028）。这 4 种 CAV 轨迹在具有相似区分度的美国独立队列中（0.97）和不同临床情况下都得到了一致的表现，且在总死亡率方面呈现梯度变化（<0.001）。
在一个大型、多中心、表型特征丰富的前瞻性心脏移植受者队列中，我们确定了 4 种 CAV 轨迹及其各自的独立预测变量。我们的研究结果为心脏移植患者的早期风险分层、患者监测和临床试验提供了基于轨迹的评估基础。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT04117152。
