Immunologic basis of cardiac disease after severe COVID-19

摘要 2019年冠状病毒病（COVID-19）由严重急性呼吸道综合征冠状病毒2（SARS- CoV-2）已成为一种广泛的全球流行病。虽然重症肌无力的主要临床表现 COVID-19是呼吸衰竭，其他器官并发症如心脏损伤是常见的。心脏损伤 和心肌病是急性疾病期间常见的心脏表现。此外，一些幸存者 COVID-19在急性疾病后几个月出现心肺症状，称为后 SARS-CoV-2急性后遗症（PASC）或“长期COVID”。考虑到心脏血管损伤的频率 COVID-19和急性疾病后长时间持续存在的症状， 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COVID-19的免疫反应导致急性炎症和损伤， 临床相关的心肌纤维化和功能障碍的长期。自2020年8月以来，我们一直 招募患者参加COVID-19免疫分析（IP）研究，其中包括采集血液的方案 COVID-19患者入院时、住院期间、1-3个月和3-12个月的标本 恢复后。我们将共同招募本研究的参与者，并进行心脏磁共振成像 (CMR)并在恢复后3-12个月和2-3年进行额外的功能性心肺评估。 我们的具体目标包括，目标1）确定严重COVID-19期间的先天免疫特征，预测长期- 心脏损伤我们将重点关注在入院时采集的血液样本中的先天免疫措施， 早期恢复，目的2）确定适应性免疫应答是否有助于COVID后的心脏损伤- 19.我们将量化针对SARS-CoV-2的反应，并探索针对SARS-CoV-2的适应不良反应。 心肌蛋白血液样本的分析将补充心脏组织的探索性研究， 和目的3）确定严重COVID-19后的长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 症状将与1-2年前感染流感的对照受试者进行比较。我们 提案回应了对COVID-19后长期心脏并发症的科学表征的迫切需求- 19.我们的合作团队拥有丰富的经验，涵盖心脏病学，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具有专长的心脏病专家领导， 和一名传染病专家，在慢性病背景下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长期心血管影响的 严重的COVID-19疾病。这些知识反过来可以帮助增进健康、延长寿命和减少疾病 和残疾。

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.