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. Author summary 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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