Identification of Transthyretin Cardiac Amyloidosis Using Serum Retinol-Binding Protein 4 and a Clinical Prediction Model.
Identification of Transthyretin Cardiac Amyloidosis Using Serum Retinol-Binding Protein 4 and a Clinical Prediction Model.
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DOI：
10.1001/jamacardio.2016.5864
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发表时间：
2017-03-01
期刊：
影响因子：
24
通讯作者：
Ruberg FL
中科院分区：
文献类型：
--
作者：
Arvanitis M;Koch CM;Chan GG;Torres-Arancivia C;LaValley MP;Jacobson DR;Berk JL;Connors LH;Ruberg FL
甲状腺素运载蛋白淀粉样心肌病（ATTR）是一个认识不足的原因，心力衰竭（HF）的老年人，部分原因是难以诊断。ATTR可能是由突变TTR蛋白引起的，该蛋白具有美国最常见的突变之一V122 I，存在于3.43%的非洲裔美国人中。确定血清视黄醇结合蛋白4（RBP 4），一种内源性TTR配体，是否可用作ATTR V122 I淀粉样变性的诊断试验。三级护理转诊中心50名年龄超过60岁的具有非淀粉样蛋白HF和心脏壁增厚的前瞻性基因分型的非裔美国人患者和活检证实的ATTR V122 I淀粉样变性患者的比较队列（n=25）组成开发队列。27例前瞻性基因分型的非裔美国人患者和9例ATTR V122 I淀粉样变性患者组成了验证队列。对所有患者的循环RBP 4、TTR、B型利钠肽（BNP）和肌钙蛋白I（TnI）浓度、心电图（ECG）、超声心动图和临床特征进行了评估。进行受试者工作特征（ROC）分析以确定ATTR V122 I淀粉样变性鉴别的最佳阈值。使用惩罚逻辑回归开发了临床预测规则，使用ROC分析进行评估，并在独立的病例和对照队列中进行验证。ATTR V122 I型淀粉样变性患者和对照组之间的年龄、性别、BNP和TnI相似。与非淀粉样蛋白对照相比，ATTR V122 I淀粉样变性患者的血清RBP 4浓度较低（31.5对49.4 μ g/ml，p < 0.001），并且在控制潜在的混杂参数后，差异持续存在。ATTR V122 I淀粉样变性患者的左心室射血分数（LVEF）较低（40% vs. 57%，p<0.001），而室间隔直径（IVSd）较高（16 vs. 14 mm，p<0.001）。ROC分析将RBP 4鉴定为ATTR V122 I淀粉样变性的敏感标识符（AUC 0.78）。由RBP 4、TTR、LVEF、IVSd、平均肢体导联ECG电压和3级舒张功能障碍组成的临床预测算法对ATTR V122 I淀粉样变性产生了极好的区分能力（AUC 0.97），而包括RBP 4浓度的4参数模型保持了极好的区分能力（AUC 0.92）。该模型在验证队列中保持了良好的区分度。采用循环RBP 4浓度和容易获得的临床参数的预测模型在病例匹配队列中准确地区分ATTR V122 I淀粉样心肌病和非淀粉样HF。我们建议，这种临床算法可能是有用的识别ATTR V122 I淀粉样变性老年人，非裔美国人心力衰竭患者。
Transthyretin amyloid cardiomyopathy (ATTR) is an under-recognized cause of heart failure (HF) in the elderly, owing in part to difficulty in diagnosis. ATTR can result from mutant TTR protein with one of the most common mutations in the United States, V122I, present in 3.43% of African Americans. To determine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis. Combined prospective and retrospective cohort study Tertiary care referral center Fifty prospectively genotyped African American patients over age 60 years with non-amyloid HF and cardiac wall thickening, and a comparator cohort of biopsy proven ATTR V122I amyloidosis patients (n=25) comprised the development cohort. Twenty-seven prospectively genotyped African American patients and 9 ATTR V122I amyloidosis patients comprised the validation cohort. Circulating RBP4, TTR, B-type natriuretic peptide (BNP) and troponin I (TnI) concentrations, electrocardiography (ECG), echocardiography, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls. Age, gender, BNP and TnI were similar between ATTR V122I amyloidosis patients and controls. Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared to non-amyloid controls (31.5 vs. 49.4 ug/ml, p < 0.001) and the difference persisted after controlling for potential confounding parameters. Left ventricular ejection fraction (LVEF) was lower in ATTR V122I amyloidosis (40% vs. 57%, p<0.001), while interventricular septal diameter (IVSd) was higher (16 vs. 14 mm, p<0.001). ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (AUC 0.78). A clinical prediction algorithm comprised of RBP4, TTR, LVEF, IVSd, mean limb lead ECG voltage and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC 0.97), while a 4 parameter model including RBP4 concentration retained excellent discrimination (AUC 0.92). The models maintained excellent discrimination in the validation cohort. A prediction model employing circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloid cardiomyopathy from non-amyloid HF in a case matched cohort. We propose that this clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly, African American patients with heart failure.