Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) is the virus responsible for COVID-19 pandemic with its origin in Wuhan, China, in December 2019. As of today April 22nd 2020, the total number of deaths from COVID-19 infection is 176,860. Epidemiological data from research studies show an uneven-handed impact on the population, with and exponential increase in disease severity and mortality in those beyond the sixth decade of life and with multiple comorbidities 1. According to a large study published by the Chinese Center for Disease Control and Prevention, as of end of Feb 11 2020, a total of 44 672 tested positive for COVID-19 infection, and among these patients several comorbidities such as cardiovascular disease, diabetes mellitus seem to be involved in COVID-19 patients with severe course. 2 In this study, 10.5% of the fatal cases occurred in patients with cardiovascular disease, 7.3% in patients with diabetes mellitus, 6% in patients with arterial hypertension, 6.3% in patients with chronic respiratory disease and 5.6% in patients with cancer.2
Angiotensin converting enzyme inhibitors (ACEI) and Angiotensin II receptors blockers (ARB) are indicated as first line treatment for patients with cardiovascular diseases and diabetes mellitus.3 The ACE inhibitors initially inhibits ACE leading to decreased angiotensin I levels, causing a possible negative feedback loop which ultimately upregulates more expression of ACE2 receptors to be able to interact with the reduced levels of the available angiotensin I.4 Researchers believe that ACE2 receptors, located on the alveolar epithelial cells, serve as a high affinity receptor and co-transporter for SARS-Cov-2 to enter the lungs. Given that ACE2 receptors are upregulated in patients who are on ACEI and ARB therapies, it was hypothesized that this increase in ACE2 expression could play a role in the severe course of COVID-19 infection in this population. This has caused significant controversy regarding the approach for patients taking ACEI/ARB amid the pandemic, with some advocating for discontinuation of these medications, while expert opinions are recommending continuation of ACEI/ARB medications, given the lack of strong clinical evidence. 1,2
First, to unravel this complex controversy, one must recognize the scarcity of data on the topic, particularly in humans. However, because of the urgency of the situation it becomes important to use inductive reasoning to make a decision toward protecting our patients. Although it is well established now that ACE2 is targeted by SARS-Cov-2 to gain entrance into cells, but, one must acknowledge that it plays a critical anti-inflammatory role in the renin-angiotensin-system (RAS), through signaling the conversion of angiotensin II, which carry pro-inflammatory effects and causes vasocontraction and hence increase in blood pressure, to Angiotensin 1-7, which carries anti-inflammatory and cardio-protective properties that can protect for subsequent lethal lung injury 1.
“What was missing in the discussion in the aforementioned dilemma is the age associated decline in ACE2 expression as observed in the lungs of the rats, which is in line with a constellation of major pro-inflammatory changes perpetrated by an age-associated increase in RAS signaling throughout the body. Exaggerated forms of this pro-inflammatory profile are also salient pathophysiologic features of hypertension and diabetes, which are highly prevalent at older ages”, says Dr. Majd Alghatrif, from the National Institute of Aging/ National Institute of Health (NIA/NIH).1
Dr. Alghatrif also explained that the upregulation of ACE2, which happens in diabetic and hypertensive patients who are treated with ACEI/ARB medications, in a way, plays a major restorative of the cardio-physiological function. Because of these paradoxical findings: given ACE2 itself is the gateway of SARS-Cov-2 into body cells, how can the reduction of ACE2 in older population predispose this population to greater COVID-19 infection? To understand this paradox clearly, we must distinguish the role ACE2 as a gateway for SARS-Cov-2 from its anti-inflammatory function in the RAS signaling pathway that is compromised in individuals with COVID-19 infection, contributing to the severity of its course in this population. It is because of the decrease of ACE2 expression and subsequent upregulation of angiotensin II expression in older individuals especially those with diabetes and hypertension, that contributes to pro-inflammatory events in this sub-population and potential cause of lethal lung injury that requires mechanical intervention. The use of ACEI/ARB medications specifically in this sub-populations increases the expression of ACE2 which plays a corrective role to these changes that occur with advance in age. These findings are consistent with the role of the RAS system and support continuing therapy with ACEI/ARB.1,2,3
Finally, given this complex dilemma, rapidly evolving nature of the disease, and the mass hysteria of social media, several cardiology associations (ACC/AHA, HFSA and ESC Hypertension Council) released an official statement regarding the continuation of ACEI/ARB for COVID-19 patients.5 The well-studied reduction in mortality conferred by ACE/ARB use and the beneficial outcomes with patients with cardiovascular disease, diabetes, chronic kidney disease and proteinuria outweigh the theoretical risk. As the COVID-19 pandemic rapidly evolves and affect more patients with cardiovascular comorbidities, further trials treating patients with severe COVID-19 with RAS interventions to examine the role of these interventions in preventing lethal lung injuries are warranted1,5,6.
- AlGhatrif M, Cingolani O, Lakatta EG. The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease: Insights From Cardiovascular Aging Science. JAMA Cardiol.Published online April 03, 2020. doi:10.1001/jamacardio.2020.1329
- The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team . The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID‐19)—China, 2020. China CDC Wkly. 2020; 2:113–122.
- Khalil H, Zeltser R. Antihypertensive Medications. [Updated 2020 Apr 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554579/
- Rico-Mesa, J.S., White, A. & Anderson, A.S. Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep22, 31 (2020). https://doi.org/10.1007/s11886-020-01291-4
- Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. 2020; 395
- Guan W.J. Ni Z.Y. Hu Y. et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;
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