Abstract

In December 2019, a novel coronavirus-related disease (Covid-19) emerged in Wuhan, China, caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). This outbreak rapidly spread throughout the world, being declared a pandemic by the world health organization on March 11, 2020. Covid-19 and other coronavirus diseases such as SARS and MERS cause serious morbidity and mortality through initiation of severe viral pneumonia often progressing to acute respiratory distress syndrome (ARDS) and multiple organ system dysfunction (MODS) (Paules et al., 2020). Non-respiratory co-morbidities such as cardiac dysfunction, renal failure, and neurological abnormalities are reported in the literature; however it is still unclear whether these are a direct result of SARS-Cov-2 invading and destroying these tissues or are more broadly related to hypoxemia, inflammation, and/or thrombosis associated with ARDS/MODS in Covid-19 patients. Currently, there are no approved antiviral therapies or vaccines available to combat Covid-19, however major efforts are ongoing worldwide to rapidly address this urgent need. Biomedical research has become fundamental in the understanding of the mechanism(s) by which SARS-CoV-2 infects its host and leads to deterioration of human health. So far, genetic analysis has revealed several similarities between SARS-CoV-2 and the virus that caused the SARS epidemic in 2002, including the molecular targets that SARS coronaviruses use to bind to their host cells (Hoffmann et al., 2020). Specifically, the SARS-CoV-2 “spike” protein binds to the type 2 angiotensin converting enzyme (ACE2) at the surface of the host cell (Hoffmann et al., 2020). ACE2 is widely expressed in the human body (found in lung, bowel, kidney, brain, blood vessels) and participates in the regulation of angiotensin II (ANGII), a potent vasoactive peptide hormone. Synthesis of ANGII depends on the catalytic activity of the type 1 angiotensin converting enzyme (ACE) and ANGII levels are modulated by the catalytic activity of ACE2 which hydrolyzes ANGII to angiotensin 1-7 (Díaz et al., 2020; Guan et al., 2020; Hoffmann et al., 2020; Huang et al., 2020; Paules et al., 2020; South et al., 2020; Yang et al., 2020), a by-product of ANGII cleavage. Thus, ACE2 activity serves to limit ANGII production and protect from the potentially damaging consequences of high levels of systemic ANGII (South et al., 2020). ACE2 is also associated with processes that attenuate inflammation, making this enzyme an interesting pharmacological target for disease processes that result in over-activation of inflammatory pathways (South et al., 2020). In early March 2020, the first epidemiological and clinical characteristics of Covid-19 patients (191 patients) were published (Huang et al., 2020). Of the total number of patients confirmed with Covid-19, 48% of total hospitalized patients in this study had significant comorbidities including hypertension (30%), diabetes (19%), and heart disease (8%). A second study with 1,099 Covid-19 patients reported that the most severe outcomes were observed in patients with hypertension, diabetes mellitus, coronary heart disease, and cerebrovascular disease (Guan et al., 2020). In a third study, out of 140 patients positive for Covid-19, 30% had hypertension and 12% had diabetes. Finally, a study by Yang et al. (2020) found that in a cohort of patients who succumbed to Covid-19, the most prevalent comorbidities were diabetes and cardiovascular disease. Of note, most of the comorbidities reported in these studies are treated with ACE inhibitors (ACEi), as increased ANGII levels are a common pathophysiological feature. Recent opinion pieces have noted that in pre-clinical studies ACEi cause up-regulation of ACE2 and theorize that this could increase susceptibility of patients currently being treated with ACEi to infection by SARS-CoV-2. This observation has led some to hypothesize that withdrawing ACEi treatment in patients with hypertension or other cardio-metabolic conditions characterized by upregulation of the renin-angiotensin system (RAS) may decrease the risk of developing severe Covid-19. While this hypothesis is worthy of further study, to our knowledge there is no evidence at this time to support removal of ACEi or other RAS-related drugs in patients for whom they are indicated. In fact, we wish to advance the hypothesis that doing so could be directly detrimental to Covid-19 related morbidity in the cohort of patients who are statistically most likely to suffer the worst outcomes. There are well-established relationships between RAS activation and autonomic dysfunction in cardio-metabolic diseases such as hypertension, heart failure, and diabetes (Díaz et al., 2020). In these conditions often a positive feedback loop exists between RAS activation and tonic increases in efferent sympathetic nerve activity, wherein increases in sympathetic activity can stimulate activation of RAS which in turn can further upregulate sympathetic activity (Díaz et al., 2020). Removal of drugs which attenuate this positive feedback loop could in fact exacerbate autonomic dysfunction and inflammation associated with these diseases, and potentially contribute to morbidity associated with Covid-19.