Sidorova Tatiana N, Mace Lisa C, Wells K Sam, Yermalitskaya Liudmila V, Su Pei-Fang, Shyr Yu, Atkinson James B, Fogo Agnes B, Prinsen Joseph K, Byrne John G, Petracek Michael R, Greelish James P, Hoff Steven J, Ball Stephen K, Glabe Charles G, Brown Nancy J, Barnett Joey V, Murray Katherine T
Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
Departments of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN (S.W.).
J Am Heart Assoc. 2014 Dec 2;3(6):e001384. doi: 10.1161/JAHA.114.001384.
Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ-specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers (PAOs) in atrial tissue has not been previously investigated.
Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAOs using a conformation-specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium-specific marker, the fraction of myocardium colocalizing with PAOs (PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAOs in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAOs in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension.
PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension.
越来越多的证据表明，蛋白毒性在实验性和人类心肌病中发挥病理生理作用。在器官特异性淀粉样变性中，可溶性蛋白质寡聚体是蛋白质聚集过程中的主要细胞毒性物质。虽然孤立性心房淀粉样变性可随年龄增长而发生，但此前尚未对心房组织中淀粉样前体寡聚体（PAO）的存在情况进行研究。
在择期心脏手术期间收集无房性心律失常、充血性心力衰竭、心肌病或淀粉样变性病史患者的心房样本。使用构象特异性抗体对PAO进行免疫组织化学检测，并对先前在孤立性心房淀粉样变性中鉴定出的候选蛋白进行检测。使用心肌特异性标志物，对与PAO共定位的心肌部分（PAO负荷）进行定量（绿色/红色比率）。从92例患者获取心房样本，平均年龄为61.7±13.8岁。大多数患者（62%）为男性，23%患有糖尿病，72%患有高血压，42%患有冠状动脉疾病。大多数患者（n = 62）接受了主动脉瓣置换术，较少患者接受冠状动脉旁路移植术（n = 34）或二尖瓣置换/修复术（n = 24）。免疫染色在大多数心房样本中检测到细胞内PAO，在整个心肌中分布不均。样本的平均绿色/红色比率值为0.11±0.1（范围0.03至0.77），74例患者的值≥0.05。心房利钠肽在心肌中与PAO共定位，而转甲状腺素蛋白位于间质中。在对多个协变量进行校正后，PAO负荷与高血压的存在独立相关。
在人类心房中经常检测到PAO，其存在与临床高血压相关。
