To the Editor

Figure 1. Figure 1. Renin–Angiotensin–Aldosterone System.

Angiotensin-converting enzyme (ACE) converts angiotensin-(1–7) (Ang 1–7) to angiotensin-(1–5) (Ang 1–5). Thus, the inhibition of ACE can lead to elevated levels of Ang 1–7. Since ACE2 also exists in a membrane-bound form and acts as a receptor when bound, it has a red outline, as do angiotensin II type 1 and type 2 (AT1 and AT2) receptors. MAS receptor denotes MAS-related G-protein–coupled receptor.

In their Special Report, Vaduganathan and colleagues (April 23 issue)1 describe the use of renin–angiotensin–aldosterone system (RAAS) inhibitors in patients with coronavirus disease 2019 (Covid-19). We would like to add the following points. First, it is worthwhile noting that studies involving in vitro human and animal cell cultures have shown that the effector peptide product of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7), is degraded by the dipeptidase ACE into angiotensin-(1–5), and ACE inhibitors increase circulating levels of angiotensin-(1–7) in patients with chronic heart failure.2 This action provides a plausible mechanism for the increase in levels of angiotensin-(1–7) mediated by ACE inhibitors. Second, if excess angiotensin II is implicated in Covid-19, there is probably a synergistic benefit in combining ACE inhibitors and angiotensin-receptor blockers (ARBs), since the latter would rapidly block the angiotensin II type 1 receptor, whereas the use of an ACE inhibitor would increase levels of angiotensin-(1–7)2,3 (Figure 1). Finally, the use of ACE inhibitors and ARBs in Covid-19 is worthy of evaluation, since these drugs are commonly used, have a low cost, and have well-recognized side effects.

John Lubel, Ph.D.
Monash University, Melbourne, VIC, Australia
[email protected]

Mayur Garg, Ph.D.
University of Melbourne, Melbourne, VIC, Australia

No potential conflict of interest relevant to this letter was reported.

This letter was published on May 19, 2020, at NEJM.org.

  1. 1. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020;382: 16531659.

  2. 2. Patel VB, Bodiga S, Fan D, et al. Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice. Hypertension 2012;59: 11951203.

  3. 3. Azizi M, Ménard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004;109: 24922499.

To the Editor

As described by Vaduganathan et al., it has been suggested that ACE2 is a major binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Covid-19. We recently observed that ACE2 expression is significantly increased in smokers with normal lung function and patients with chronic obstructive pulmonary disease (COPD), whereas similar healthy controls showed no or sparse expression.1 Specifically, we found that ACE2 expression was highly up-regulated in the small airway epithelium, including cilia, type 2 pneumocytes, and alveolar macrophages.1 These findings were recently confirmed in a larger cohort.2 Both studies indicated that smoking up-regulates ACE2 expression and that COPD further exaggerates Covid-19 susceptibility. Patients with cardiovascular disease, hypertension, and diabetes who are infected with SARS-CoV-2 may have more severe clinical consequences, and many patients who are smokers or who have COPD also have these conditions.3,4 We wonder whether smokers and patients with COPD should be prescribed ACE2 inhibitors in general practice to reduce the risks associated with Covid-19.

Greg Haug, M.D.
Launceston General Hospital, Launceston, TAS, Australia

Mathew S. Eapen, Ph.D.
Sukhwinder S. Sohal, Ph.D.
University of Tasmania, Launceston, TAS, Australia
[email protected]

No potential conflict of interest relevant to this letter was reported.

This letter was published on May 19, 2020, at NEJM.org.

  1. 1. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, Sohal SS. Smoking upregulates angiotensin-converting enzyme-2 receptor: a potential adhesion site for novel coronavirus SARS-CoV-2 (Covid-19). J Clin Med 2020;9: 841841.

  2. 2. Leung JM, Yang CX, Tam A, et al. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J 2020 April 8 (Epub ahead of print).

  3. 3. Barnsley K, Sohal SS. Covid-19 and smoking: the elephant in the room? BMJ Blog: tobacco control. March 24, 2020 (https://blogs.bmj.com/tc/2020/03/24/covid-19-and-smoking-the-elephant-in-the-room/).

  4. 4. Barnsley K, Sohal SS. COVID-19, propelled by smoking, could destroy entire nations. European Respiratory Society. March 30, 2020 (https://www.ersnet.org/covid-19-blog/covid-19–propelled-by-smoking–could-destroy-entire-nations).

To the Editor

Vaduganathan and colleagues consider the roles that ACE inhibitors and ARBs may play in outcomes of SARS-CoV-2 infection but do not consider the role of aldosterone-receptor blockade (e.g., with spironolactone). The single figure in their article does not include the mineralocorticoid aldosterone or its receptor.

SARS-CoV-2 uses the ACE2 receptor to enter pneumocytes. The finding that spironolactone increases levels of ACE2 messenger RNA in humans1 raises concern regarding increased infectious susceptibility caused by that medication, which is in widespread use for hypertension but also for hyperandrogenic conditions,2 such as hirsutism, acne vulgaris, androgenetic alopecia, polycystic ovary syndrome, and hidradenitis suppurativa.3 However, the use of spironolactone and elevated ACE2 expression may prevent the consequences of organ damage4 in patients with Covid-19 infection through the inhibition of angiotensin II and its effects. These findings suggest the hypothesis that spironolactone could increase the incidence of infection while diminishing the severity of disease in individual patients.

The advisability of changing spironolactone use during the pandemic remains unclear but should not be overlooked. The discontinuation of ACE inhibitors and ARBs may exacerbate hypertension, which argues against stopping these medications. However, such decisions regarding spironolactone may be less clear with respect to its antiandrogenic indications.

Ron A. Birnbaum, M.D.
Los Angeles County Harbor–UCLA Medical Center, Los Angeles, CA
[email protected]

No potential conflict of interest relevant to this letter was reported.

This letter was published on May 19, 2020, at NEJM.org.

  1. 1. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111: 26052610.

  2. 2. Schmidt TH, Shinkai K. Evidence-based approach to cutaneous hyperandrogenism in women. J Am Acad Dermatol 2015;73: 672690.

  3. 3. Golbari NM, Porter ML, Kimball AB. Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa. J Am Acad Dermatol 2019;80: 114119.

  4. 4. Sato A, Saruta T, Funder JW. Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection. Hypertens Res 2006;29: 211216.

Response

The authors reply: Angiotensin peptides exist in dynamic equilibrium that varies across species, tissue beds, and pathologic states, which in turn may influence their biologic responses to pharmacologic modulation. Lubel and Garg propose that ACE inhibitors may increase angiotensin-(1–7) levels by attenuating its breakdown to angiotensin-(1–5) on the basis of preclinical models. However, intravenous administration of ACE inhibitors did not influence angiotensin-(1–7) levels in patients with coronary artery disease.1 Furthermore, in comparisons with ACE inhibitors or ARBs alone, dual inhibition of the renin–angiotensin system has not provided incremental benefits and has resulted in safety issues when tested in large clinical trials involving high-risk patients in other situations.2

Local and systemic RAAS activation has been posited as one mechanism underlying the effects of Covid-19. Initial observational data have suggested that RAAS inhibitors may not be associated with excess risk3 and may even be associated with benefit in Covid-19.4 Multiple trials are under way to evaluate the administration of RAAS inhibitors in patients with Covid-19 who had not previously received these drugs and strategies of continuation versus withdrawal of RAAS inhibitors in previously treated patients. In addition, a modest-sized trial (ClinicalTrials.gov number, NCT04335136) is evaluating the therapeutic effects of recombinant human ACE2 in Covid-19. An adaptive trial (NCT04332666) is also testing the use of intravenous angiotensin-(1–7) infusion in patients with Covid-19 complicated by severe respiratory failure.

Haug and colleagues suggest that the up-regulation of pulmonary ACE2 in response to environmental and disease exposures (e.g., smoke inhalation and COPD) may be important in SARS-CoV-2 susceptibility and may, in part, account for the increased risk in these populations. Although pulmonary ACE2 expression may be subject to diverse inputs, in many cases, these factors are also determinants of overall health and may confound the relationship between ACE2 and outcomes in patients with Covid-19.

Finally, in our article, we focused on ACE inhibitors and ARBs, since they are the most widely used RAAS inhibitors worldwide. However, as Birnbaum points out, mineralocorticoid receptor antagonists5 may similarly increase the expression of ACE2 and yet may also mitigate the adverse downstream consequences of RAAS activation. As with ACE inhibitors and ARBs, the relevance of these putative effects is uncertain. Thus, we think that until more data are available, these therapies that are used for other established indications should also be continued in patients with Covid-19 whose condition is otherwise stable.

Muthiah Vaduganathan, M.D., M.P.H.
Scott D. Solomon, M.D.
Brigham and Women’s Hospital, Boston, MA
[email protected]

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on May 19, 2020, at NEJM.org.

  1. 1. Campbell DJ, Zeitz CJ, Esler MD, Horowitz JD. Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens 2004;22: 19711976.

  2. 2. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358: 15471559.

  3. 3. Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol 2020 April 23 (Epub ahead of print).

  4. 4. Zhang P, Zhu L, Cai J, et al. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res 2020 April 17 (Epub ahead of print).

  5. 5. Keidar S, Gamliel-Lazarovich A, Kaplan M, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res 2005;97: 946953.

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