We recently described a subgroup of autopsied COVID-19 subjects (∼40%), termed ‘profibrotic phenotype,’ who exhibited clusters of myofibroblasts (Mfbs), which were positive for the collagen-specific chaperone heat shock protein 47 (HSP47⁺) in situ. This report identifies increased, localized (hot spot restricted) expression of αSMA, COLα1, POSTN and FAP supporting the identity of HSP47⁺ cells as myofibroblasts and characterizing a profibrotic extracellular matrix (ECM) phenotype. Coupled with increased GRP78 in COVID-19 subjects, these data could reflect induction of the unfolded protein response for mitigation of proteostasis (i.e., protein homeostasis) dysfunction in discrete clusters of cells. ECM shifts in selected COVID-19 subjects occur without significant increases in either global trichrome positive staining or myocardial injury based quantitively on standard H&E scoring. Our findings also suggest distinct mechanism(s) for ECM remodeling in the setting of SARS-CoV-2 infection. The ratio of CD163⁺/CD68⁺ cells is increased in hot spots of profibrotic hearts compared with either controls or outside of hot spots in COVID-19 subjects. In sum, matrix remodeling of human COVID-19 hearts in situ is characterized by site-restricted profibrotic mediated (e.g., HSP47⁺ Mfbs, CD163⁺ Mφs) modifications in ECM (i.e., COLα1, POSTN, FAP), with a strong correlation between COLα1 and HSP47⁺cells within hot spots. Given the established associations of viral infection (e.g., human immunodeficiency virus; HIV), myocardial fibrosis and sudden cardiac death, early screening tools (e.g., plasma biomarkers, noninvasive cardiac magnetic resonance imaging) for diagnosis, monitoring and treatment of fibrotic ECM remodeling are warranted for COVID-19 high-risk populations.

我们最近描述了一组尸检的 COVID-19 受试者（约 40%），被称为“促纤维化表型”，他们表现出肌成纤维细胞 (Mfbs) 簇，这些细胞对胶原蛋白特异性伴侣热休克蛋白 47 (HSP47 ⁺ )呈阳性。现场。该报告确定了 αSMA、COLα1、POSTN 和 FAP 的局部（热点限制）表达增加，支持 HSP47 ⁺细胞作为肌成纤维细胞的身份，并表征了促纤维化细胞外基质 (ECM) 表型。加上 COVID-19 受试者中 GRP78 的增加，这些数据可以反映诱导未折叠蛋白反应，以减轻离散细胞簇中的蛋白质稳态（即蛋白质稳态）功能障碍。根据标准 H&E 评分，选定的 COVID-19 受试者发生 ECM 变化，但整体三色阳性染色或心肌损伤并未显着增加。我们的研究结果还表明了 SARS-CoV-2 感染背景下 ECM 重塑的独特机制。与对照组或 COVID-19 受试者的热点之外相比，促纤维化心脏热点中CD163 ⁺ /CD68 ⁺细胞的比率有所增加。总之，人 COVID-19 心脏原位基质重塑的特点是 ECM（即 COLα1、POSTN、FAP）中位点限制性促纤维化介导的（例如 HSP47 ⁺ Mfbs、CD163 ⁺ Mφs）修饰，并且与热点内的COLα1 和 HSP47 ^+细胞。鉴于病毒感染（例如，人类免疫缺陷病毒；HIV）、心肌纤维化和心源性猝死之间已确定的关联，用于诊断、监测和治疗纤维化 ECM 重塑的早期筛查工具（例如，血浆生物标志物、无创心脏磁共振成像）正在开发中。适用于 COVID-19 高危人群。