University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Clinical and Experimental Cardiology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology, Groningen, The Netherlands.
University Medical Center Utrecht, Department of Pathology, Utrecht, The Netherlands.
Cardiovasc Pathol. 2017 Sep-Oct;30:23-26. doi: 10.1016/j.carpath.2017.05.004. Epub 2017 May 30.
Phospholamban (PLN) p.Arg14del cardiomyopathy is associated with an increased risk of malignant ventricular arrhythmias and severe heart failure and a poor prognosis from late adolescence. It can be diagnosed in whole heart specimens, but rarely in right ventricular biopsy specimens, by PLN immunohistochemistry showing PLN-containing aggregates concentrated in cardiomyocytes in dense perinuclear aggresomes. The purpose of this study was to determine whether PLN immunohistochemistry can be used to diagnose PLN p.Arg14del cardiomyopathy using apical left ventricular myocardial specimens harvested during left ventricular assist device (LVAD) implantation. At that stage, a genetic diagnosis, which may guide treatment and referral of family members for further investigation, is frequently not established yet. Included were myocardial specimens from 30 diverse genetic cardiomyopathy cases with known variants (9 carriers of the pathogenic PLN p.Arg14del variant, 18 cases with other pathogenic or likely pathogenic variants in cardiomyopathy-related genes, and 3 with only variants of unknown significance). Immunohistochemical analysis revealed typical dense perinuclear globular PLN-positive aggregates, representing aggresomes, in all nine PLN p.Arg14del cases. In 20 non-PLN cases, PLN-staining was absent. In one non-PLN case, one of the two independent observers misinterpreted PLN staining of heavily wrinkled nuclear membranes of cardiomyocytes as perinuclear PLN aggregates. In this genetic cardiomyopathy cohort, PLN Immunohistochemical analysis in LVAD biopsies was found to be a highly sensitive (100%) and specific (95%) method for demonstration of PLN protein aggregates in PLN p.Arg14del cardiomyopathy. In clinical practice, PLN immunohistochemical analysis of LVAD specimens can be of incremental value in the diagnostic workup of this cardiomyopathy, even more so if genetic analysis is not readily available.
磷酸化肌浆球蛋白结合蛋白（PLN）p.Arg14del 心肌病与恶性室性心律失常、严重心力衰竭的风险增加以及从青春期后期开始的预后不良相关。通过 PLN 免疫组化可以在全心标本中，但很少在右心活检标本中诊断出这种疾病，表现为富含 PLN 的聚集体集中在致密核周聚集物中的心肌细胞内。本研究旨在确定 PLN 免疫组化是否可用于诊断 PLN p.Arg14del 心肌病，使用的是在左心室辅助装置（LVAD）植入期间采集的左室心尖心肌标本。在该阶段，通常尚未确定遗传诊断，遗传诊断可能指导治疗并转介家庭成员进行进一步调查。纳入了 30 个不同的遗传性心肌病病例的心肌标本，这些病例具有已知的变体（9 个携带致病性 PLN p.Arg14del 变体的病例，18 个携带与心肌病相关基因的其他致病性或可能致病性变体的病例，以及 3 个仅具有未知意义变体的病例）。免疫组化分析显示，在所有 9 个 PLN p.Arg14del 病例中，均存在典型的致密核周球状 PLN 阳性聚集体，代表聚集物。在 20 个非 PLN 病例中，PLN 染色不存在。在一个非 PLN 病例中，两位独立观察者中的一位错误地将心肌细胞皱缩核膜的 PLN 染色解释为核周 PLN 聚集体。在这个遗传性心肌病队列中，发现 LVAD 活检中的 PLN 免疫组化分析是一种高度敏感（100%）和特异（95%）的方法，可用于显示 PLN p.Arg14del 心肌病中的 PLN 蛋白聚集体。在临床实践中，即使遗传分析不易获得，PLN 免疫组化分析 LVAD 标本也可以为该心肌病的诊断工作提供附加价值。
