Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers During the COVID-19 Pandemic: A Modeling Analysis.
Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers During the COVID-19 Pandemic: A Modeling Analysis.
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DOI：
10.1371/journal.pcbi.1008235
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发表时间：
2020-10
影响因子：
4.3
通讯作者：
Layton AT
中科院分区：
文献类型：
--
作者：
Sadria M;Layton AT
血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）经常用于一系列疾病，包括高血压、蛋白尿慢性肾病和心力衰竭。有证据表明，这些药物上调ACE2， ACE2是肾素血管紧张素系统（RAS）的关键成分，存在于包括肺上皮细胞在内的许多组织的细胞中。虽然ACE2在高血压、糖尿病和心血管疾病等许多疾病中都有有益的作用，但它也通过与病毒的刺突蛋白结合，成为SARS-CoV和SARS-CoV-2的受体，从而允许其进入宿主细胞。因此，有人认为，这些疗法理论上会增加SARS- CoV-2感染的风险，并导致更严重的COVID-19。鉴于ACEi和arb在心血管疾病中的成功，我们寻求深入了解这些药物在COVID-19发病机制中的意义。为此，我们开发了一个数学模型，可以代表RAS、ACE2与SARS-CoV-2的结合以及随后的细胞进入，以及宿主的急性炎症反应。该模型可以模拟不同水平的SARS-CoV-2暴露，并代表常用抗高血压药物、ACEi和ARB的效果，并预测组织损伤。模型模拟表明，ACEi或ARB治疗是否会加重组织损伤程度取决于多种因素，包括现有炎症水平、剂量以及药物对ACE2蛋白丰度的影响。这项研究的结果可以作为在当前和未来冠状病毒大流行中制定适当和更全面的ACEi和ARB处方指南的第一步。在我们准备应对2019冠状病毒病大流行的破坏性影响之际，我们必须解决关于如何最大限度地减少最弱势群体感染致命疾病风险的争议。初步流行病学数据显示，心血管疾病和糖尿病患者的疾病严重程度和死亡率呈指数增长。冠状病毒通过与细胞膜上的一种特定酶ACE2结合进入宿主细胞。血管紧张素转换酶抑制剂（ACEi）和血管紧张素II受体阻滞剂（ARB）两类药物治疗的心血管疾病和糖尿病患者的ACE2丰度增加。这引起了关于大流行期间患者服用这些药物的方法的争议，一些人主张停止使用这些药物，而专家意见则建议由于缺乏强有力的证据而不停止使用这些药物。鉴于ACEi和arb在心血管疾病中的成功，我们的目标是帮助患者和医生权衡总体利弊。为了实现这一目标，我们开发了冠状病毒入侵和宿主免疫反应的数学模型。模型模拟表明，在接受ACEi或ARB治疗的患者中，COVID-19引起的组织损伤程度取决于许多因素，包括任何现有慢性炎症的水平、剂量和某些药物的作用。
Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are frequently prescribed for a range of diseases including hypertension, proteinuric chronic kidney disease, and heart failure. There is evidence indicating that these drugs upregulate ACE2, a key component of the renin-angiotensin system (RAS) and is found on the cells of a number of tissues, including the epithelial cells in the lungs. While ACE2 has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease, it also serves as a receptor for both SARS-CoV and SARS-CoV-2 via binding with the spike protein of the virus, thereby allowing it entry into host cells. Thus, it has been suggested that these therapies can theoretically increase the risk of SARS- CoV-2 infection and cause more severe COVID-19. Given the success of ACEi and ARBs in cardiovascular diseases, we seek to gain insights into the implications of these medications in the pathogenesis of COVID-19. To that end, we have developed a mathematical model that represents the RAS, binding of ACE2 with SARS-CoV-2 and the subsequent cell entry, and the host’s acute inflammatory response. The model can simulate different levels of SARS-CoV-2 exposure, and represent the effect of commonly prescribed anti-hypertensive medications, ACEi and ARB, and predict tissue damage. Model simulations indicate that whether the extent of tissue damage may be exacerbated by ACEi or ARB treatment depends on a number of factors, including the level of existing inflammation, dosage, and the effect of the drugs on ACE2 protein abundance. The findings of this study can serve as the first step in the development of appropriate and more comprehensive guidelines for the prescription of ACEi and ARB in the current and future coronavirus pandemics. As we brace for the devastating impact of the COVID-19 pandemic, we must tackle a controversy on how to best minimize the risk of lethal disease among the most vulnerable. Preliminary epidemiological data show an exponential increase in disease severity and mortality among patients with cardiovascular disease and diabetes. The coronavirus enters host cells by binding to a specific enzyme “ACE2” on the cell membrane. ACE2 abundance is increased in patients with cardiovascular disease and diabetes treated with two classes of drugs: angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB). This has generated controversy regarding the approach for patients taking these drugs during the pandemic, with some advocating for discontinuing these medications, while expert opinions recommended against discontinuation, given the lack of strong evidence. Given the success of ACEi and ARBs in cardiovascular diseases, we aim to help patients and physicians weigh the overall pros and cons. To achieve that goal, we have developed a mathematical model of the invasion of the coronavirus and the host’s immune response. Model simulations indicate how much tissue damage COVID-19 induces in a patient undergoing ACEi or ARB treatment depends on a number of factors, including the level of any existing chronic inflammation, dosage, and certain drugs effects.
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