Table_1_Controversial Roles of the Renin Angiotensin System and Its Modulators During the COVID-19 Pandemic.docx

Since December 2019, the coronavirus 2019 (COVID-19) pandemic has rapidly spread and overwhelmed healthcare systems worldwide, urging physicians to understand how to manage this novel infection. Early in the pandemic, more severe forms of COVID-19 have been observed in patients with cardiovascular comorbidities, who are often treated with renin-angiotensin aldosterone system (RAAS)-blockers, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), but whether these are indeed independent risk factors is unknown. The cellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the membrane-bound angiotensin converting enzyme 2 (ACE2), as for SARS-CoV(-1). Experimental data suggest that expression of ACE2 may be increased by RAAS-blockers, raising concerns that these drugs may facilitate viral cell entry. On the other hand, ACE2 is a key counter-regulator of the RAAS, by degrading angiotensin II into angiotensin (1-7), and may thereby mediate beneficial effects in COVID-19. These considerations have raised concerns about the management of these drugs, and early comments shed vivid controversy among physicians. This review will describe the homeostatic balance between ACE-angiotensin II and ACE2-angiotensin (1-7) and summarize the pathophysiological rationale underlying the debated role of the RAAS and its modulators in the context of the pandemic. In addition, we will review available evidence investigating the impact of RAAS blockers on the course and prognosis of COVID-19 and discuss why retrospective observational studies should be interpreted with caution. These considerations highlight the importance of solid evidence-based data in order to guide physicians in the management of RAAS-interfering drugs in the general population as well as in patients with more or less severe forms of SARS-CoV-2 infection.

自2019年12月以来，2019冠状病毒病（coronavirus 2019, COVID-19）大流行快速蔓延，致使全球医疗卫生系统濒临崩溃，促使临床医师亟需明确如何规范诊疗这一新型感染性疾病。疫情早期，合并心血管基础疾病的患者中更易出现重症COVID-19病例，此类患者常接受肾素-血管紧张素-醛固酮系统（renin-angiotensin aldosterone system, RAAS）阻断剂治疗，例如血管紧张素转换酶抑制剂（angiotensin-converting enzyme inhibitors, ACEIs）或血管紧张素Ⅱ受体拮抗剂（angiotensin receptor blockers, ARBs），但上述药物是否确实为COVID-19的独立危险因素目前尚无定论。与严重急性呼吸综合征冠状病毒1型（SARS-CoV-1）一致，严重急性呼吸综合征冠状病毒2型（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）的细胞受体为膜结合型血管紧张素转换酶2（membrane-bound angiotensin converting enzyme 2, ACE2）。实验数据表明，RAAS阻断剂可上调ACE2的表达，由此引发了此类药物可能促进病毒侵入宿主细胞的担忧。另一方面，ACE2是RAAS的关键负向调节因子，可将血管紧张素Ⅱ降解为血管紧张素(1-7)，从而可能在COVID-19病程中发挥有益作用。上述争议点引发了临床医师对该类药物管理方案的广泛讨论，早期相关评论在临床医师群体中掀起了激烈的学术争论。本综述将阐述ACE-血管紧张素Ⅱ与ACE2-血管紧张素(1-7)之间的稳态平衡，并总结在本次新冠大流行背景下，RAAS及其调节剂所存争议的病理生理学理论基础。此外，我们将梳理现有关于RAAS阻断剂对COVID-19病程及预后影响的研究证据，并讨论为何需谨慎解读回顾性观察性研究。上述考量凸显了基于确凿循证医学数据的重要性，以指导临床医师在普通人群以及不同病情严重程度的SARS-CoV-2感染者中合理使用干扰RAAS的药物。