Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19.
Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19.
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DOI：
10.1172/jci.insight.154633
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发表时间：
2022-01-25
期刊：
影响因子：
8
通讯作者：
Tsai EJ
中科院分区：
文献类型：
--
作者：
Brener MI;Hulke ML;Fukuma N;Golob S;Zilinyi RS;Zhou Z;Tzimas C;Russo I;McGroder C;Pfeiffer RD;Chong A;Zhang G;Burkhoff D;Leon MB;Maurer MS;Moses JW;Uhlemann AC;Hibshoosh H;Uriel N;Szabolcs MJ;Redfors B;Marboe CC;Baldwin MR;Tucker NR;Tsai EJ
急性心脏损伤在COVID-19危重患者中很普遍，并与死亡率增加有关。其病因仍有争议，因为最初推测的原因-心肌炎和心肌坏死-已被证明罕见。为了阐明COVID-19相关心脏损伤的病理生理学，我们对纽约市CUIMC连续69例COVID-19患者进行了前瞻性研究。在6种急性心脏组织病理学特征中，微血栓的存在是我们队列中最常见的。我们检测了心脏微血栓与炎症、心脏损伤和纤溶生物标志物的相关性，以及与院内抗血小板治疗、治疗性抗凝和皮质类固醇治疗的相关性，同时调整了包括COVID-19治疗在内的多种临床因素。较高的峰值红细胞沉降率和c反应蛋白与微血栓的几率增加独立相关，支持免疫血栓的病因学。通过对3例心脏微血栓患者和4例无心脏微血栓患者的单核rna测序分析，研究人员发现，相对于微血栓阴性心脏，微血栓阳性心脏成纤维细胞中血栓形成前/抗纤溶、细胞外基质重塑和免疫增强信号的富集。非covid -19、未衰竭的心脏作为参考对照。我们的研究确定了心脏成纤维细胞中特定的转录组特征，这是微血栓阳性COVID-19心脏的一个显著特征。我们的发现需要进一步的机制研究，因为心脏成纤维细胞可能是covid -19相关心脏微血栓的潜在治疗靶点。
Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes — myocarditis and cardiac necrosis — have proved uncommon. To elucidate the pathophysiology of COVID-19–associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non–COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19–associated cardiac microthrombi.