Immunologic basis of cardiac disease after severe COVID-19

摘要 严重急性呼吸系统综合症冠状病毒引起的2019年冠状病毒病(新冠肺炎) CoV-2)已成为一种广泛的全球大流行。而重症肺炎的主要临床表现 新冠肺炎是一种呼吸衰竭，心脏损伤等其他器官并发症也很常见。心脏损伤 和心肌病是急性疾病中常见的心脏表现。此外，一些幸存者 新冠肺炎在患上这种急性疾病几个月后出现心肺症状，称为后 SARS-CoV-2(PASC)或“长冠状病毒病”的急性后遗症。考虑到心血管损伤的频率 而新冠肺炎症状持续较长时间后出现急症，有急症 需要研究SARS-CoV-2对心血管系统的晚期影响。我们的目标是调查 中心假设：对严重新冠肺炎的免疫反应会导致急性炎症和损伤，从而 与临床相关的长期心肌纤维化和功能障碍。自2020年8月以来，我们一直在 将患者纳入新冠肺炎免疫简档(IP)研究，其中包括采集血液的协议 新冠肺炎患者入院时、住院期间、1-3个月和3-12个月的标本 在康复之后。我们将联合招募这项研究的参与者并进行心脏磁共振成像 在康复后3~12个月和2~3年分别进行CMR和附加心肺功能评估。 我们的具体目标包括：目标1)识别严重新冠肺炎期间的先天性免疫特征，预测长期- 严重的心脏损伤。我们将重点采取入院时和入院时采集的血液样本的先天免疫措施 早期康复，目的2)确定获得性免疫反应是否有助于COVID后的心脏损伤- 19.我们将量化针对SARS-CoV-2的反应，并探索以适应不良反应为目标 心脏蛋白质。血液样本的分析将辅之以心脏组织的探索性研究， 目的3)确定严重新冠肺炎后的远期心脏结构和功能异常。 这包括心脏纤维化和功能障碍、心肺功能障碍和临床的特征。 症状。将与1-2年前感染过流感的对照组参与者进行比较。我们的 该提案回应了对COVID后长期心脏并发症的科学表征的迫切需要- 19.我们的协作团队在心脏病学、传染病、免疫学、 和流行病学，并将由一位在CMR和炎症性心肌病方面拥有专业知识的心脏病专家领导， 以及传染病专家，在慢性心脏病方面具有心血管并发症方面的专业知识 病毒感染。我们的工作的成功完成将有助于了解 严重的新冠肺炎病。这些知识反过来可以帮助增进健康、延长寿命和减少疾病 新冠肺炎幸存者的残疾。

ABSTRACT Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) has become a widespread global pandemic. While the predominant clinical manifestation of severe COVID-19 is respiratory failure, other organ complications such as cardiac injury are common. Cardiac injury and cardiomyopathy are frequent cardiac manifestations during acute illness. Additionally, some survivors of COVID-19 are experiencing cardiopulmonary symptoms months after the acute illness, referred to as Post- Acute Sequelae of SARS-CoV-2 (PASC) or “Long COVID”. Given the frequency of cardiovascular injury during COVID-19 and the persistence of symptoms for extended periods after the acute illness, there is an urgent need for studies of the late effects of SARS-CoV-2 on the cardiovascular system. We aim to investigate the central hypothesis that immune responses to severe COVID-19 cause acute inflammation and injury that result in clinically relevant myocardial fibrosis and dysfunction over the long-term. Since August 2020, we have been enrolling patients in a COVID-19 Immune Profiling (IP) Study, which includes a protocol to collect blood specimens from patients with COVID-19 at admission, during hospitalization, 1-3 months, and 3-12 months after recovery. We will co-enroll participants from this study and perform cardiac magnetic resonance imaging (CMR) and additional functional cardiopulmonary assessments at 3-12 months and 2-3 years after recovery. Our specific aims include, Aim 1) Identify innate immune profiles during severe COVID-19 that predict long- term cardiac damage. We will focus innate immunity measures in blood specimens collected at admission and early recovery, Aim 2) Establish whether adaptive immune responses contribute to cardiac injury after COVID- 19. We will quantify responses targeting SARS-CoV-2 as well as explore maladaptive responses targeting cardiac proteins. Analysis of blood specimens will be supplemented with exploratory studies of cardiac tissue, and Aim 3) Determine the long-term structural and functional cardiac abnormalities after severe COVID-19. This includes characterization of cardiac fibrosis and dysfunction, cardiopulmonary dysfunction, and clinical symptoms. Comparisons will be made with control participants who had influenza infection 1-2 years prior. Our proposal responds to urgent need for science characterizing long-term cardiac complications following COVID- 19. Our collaborative team has extensive experience spanning cardiology, infectious disease, immunology, and epidemiology, and will be led by a cardiologist with expertise in CMR and inflammatory cardiomyopathies, and an infectious diseases specialist with expertise in cardiovascular complications in the context of chronic viral infections. Successful completion of our work will help understand the long-term cardiovascular effects of severe COVID-19 illness. This knowledge could, in turn, help enhance health, lengthen life, and reduce illness and disability in COVID-19 survivors.