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Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1091 (Published 26 March 2020) Cite this as: BMJ 2020;368:m1091

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Inhibitors of the renin-angiotensin-aldosterone system and CoViD-19-affected patients: A two-faced Janus?

Inhibitors of the renin-angiotensin-aldosterone system and CoViD-19-affected patients: A two-faced Janus?

Adriana Albini (1), Giovanni Di Guardo (2)* and Michele Lombardo (3)

1) Scientific and Technology Pole, IRCCS Multimedica, Milan, Italy; 2) University of Teramo, Faculty of Veterinary Medicine, Teramo, Italy; 3) Cardiology Unit, San Giuseppe Hospital-MultiMedica, Milan, Italy; *Corresponding author (E-mail address: gdiguardo@unite.it)

Dear Editor,
We have read the interesting article by Dr Chen and coworkers (1), reporting that hypertension and other cardiovascular comorbidities in CoViD-19 (CoronaVirus Disease 2019)-affected patients occurred in deceased subjects with a frequency approximately twice that seen in recovered ones. In this respect, among over 9,000 SARS-CoV-2-infected patients in Italy who succumbed, 73% were hypertensive, 28% suffered from ischemic heart disease and 31% were diabetic, with their median age being 78 years, in comparison to 63 years of those surviving (2). This may contribute to explain the increased CoViD-19-associated/related mortality rate in Italy (10.5%) as compared to that (2.5%) reported in infected cohorts from China (3). In Chinese cohorts, the most prevalent comorbidities are hypertension (24%), diabetes (16%) and cardiovascular disease (CVD) conditions (9%) (4). In another study by Dr Wu and coworkers (5), focused on 201 SARS-CoV-2-infected patients, the median age was 51 years and, among the 42% of them who developed acute respiratory distress syndrome, 27% had hypertension, 19% diabetes and 52% died. These observations pave the way to several issues of relevant concern. In this respect, while SARS-CoV-2-infected patients of older age with CVD comorbidities show a more severe clinical course and a worse prognosis, it should be adequately underscored that many of these patients in Italy are currently treated with ACE-inhibitors or angiotensin II receptor blockers (ARBs), which are considered the drugs of first choice for hypertension and other CVD conditions (6). Furthermore, the impact of SARS-CoV-2 infection on the cardiovascular system, highlighted by the occurrence of myocarditis, coronary plaque instability and myocardial infarction, coupled with heart failure exacerbation, makes a significant contribution to mortality in elderly patients (7). The antagonists of the renin-angiotensin-aldosterone system (RAAS) have been shown to interfere with angiotensin converting enzyme (ACE)-2 receptor expression in heart and kidney tissues. Therefore, are the aforementioned factors and conditions able to shape the clinical course of SARS-CoV-2 infection in CVD comorbid individuals? In other words, should these "intrinsically weaker" patients maintain or discontinue their ACE-inhibitor or ARB-based therapeutic regimens?
As already shown for SARS-CoV, the viral pathogen responsible for severe acute respiratory syndrome (SARS), ACE2 is the main cell receptor also for SARS-CoV-2. Within such framework, valuable insights into the molecular bases driving the complex interactions occurring at the SARS-CoV-2/ACE2 interface have been recently provided (8,9). Still noteworthy, experimental studies carried out both in vivo and in vitro have reported conflicting results. Indeed, normotensive rats treated with the ACE-inhibitor lisinopril and with the ARB losartan were shown to develop an increased cardiac ACE2 expression (10). By contrast, an ACE2 downregulation at mRNA and protein levels was reported in kidney and heart tissues from patients treated with ACE-inhibitors and ARBs (11).
Taken together, these experimental data add further concern to the fear that ACE-inhibitor or ARB-based treatments could worsen the prognosis of SARS-CoV-2 infection in patients suffering from simultaneously occurring CVD conditions. As a matter of fact, it has been additionally claimed that the ACE2 upregulation putatively induced by these two drug classes, although elicited through different mechanisms, could favour SARS-CoV-2 human lung tissue colonization (12). Conversely, it has been also hypothesized that ARBs could result potentially useful in the clinical course of SARS-CoV-2-infected patients (13).
A recently released HFSA/AAC/AHA Statement has emphasized the need to continue ongoing treatments with RAAS antagonists in patients assuming these drugs, despite the herein highlighted concerns that their use might worsen CoViD-19 evolution and outcome in SARS-CoV-2-infected subjects (14).
Within such context, the data originating from the aforementioned studies might suggest that previously or concurrently administered treatments based upon ACE-inhibitors or ARBs could influence the clinical course of SARS-CoV-2-infection.
Given the aforementioned "dual" effects of ACE- inhibitors and ARBs on ACE2 expression, which could be defined a “two-faced Janus”, we strongly believe that a body of solid and robust , "science-evidence"-based data are urgently needed, in order to provide a "non-equivocal" reply to the crucial question whether RAAS antagonists can be safey maintained or removed in handling elderly, hypertensive, diabetic or cardiovascular comorbidity-affected, SARS-CoV-2-infected patients.
In this respect, we herein emphasize the cogent need of adequately funded studies aimed at evaluating the real impact, if any, of ACE-inhibitor and ARB drugs on SARS-CoV-2 infection's clinico-pathological evolution and outcome.
Last but not least, the post mortem investigations which will be performed (as much as possible, most hopefully!) on deceased patients with CoViD-19, will be of paramount relevance for providing adequate, science evidence-based answers to the many open issues concerning SARS-CoV-2 infection's pathogenesis, including those addressed in the present Letter to the Editor.

References

1. Chen T., et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091.

2. Report sulle caratteristiche dei pazienti deceduti positivi a COVID-19 in Italia. Italian ISS Report, March 26, 2020.

3. Deng S.Q, Peng H.J. Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China. J Clin Med 2020;9.

4. Guan W., et al. Clinical caracteristics of coronarovirus in China, N Engl J Med 2020;doi:10.1056Moa20020.

5. Wu C., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with CoronaroVirus Disease 2019 Pneumonia in Wuhan, China, JAMA Intern Med. 2020;doi:10.1001/jamainternmed.20200994.

6. Williams B., et al.. 2018 ESC/ESH Guidelines for the Management of Arterial Hypertension. Eur Heart J 2018;39: 3021-3104.

7. Xiong T.-Y., et al. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J 2020;doi: 10.1093/eurheartj/ehaa231.

8. Yan R., et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020.

9. Hoffmann M., et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020.

10. Ferrario C.M., et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin converting enzyme 2. Circulation 2005;24:2605-2010.

11. Koka M., et al. Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol 2008;172:1174-1183.

12. Fang L., Karakiulakis G., Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020.

13. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020.

14. American College of Cardiology (AAC News Story). HFSA/AAC/AHA Statement adresses concerns: Using RAAS antagonists in CoViD-19, March 2020.

Competing interests: No competing interests

28 March 2020
Giovanni Di Guardo
Professor of General Pathology and Veterinary Pathophysiology
Adriana Albini, Scientific and Technology Pole, IRCCS Multimedica, Milan, Italy; Michele Lombardo, San Giuseppe Hospital-Multimedical, Milan, Italy
University of Teramo, Faculty of Veterinary Medicine
University of Teramo, Faculty of Veterinary Medicine, Localita' Piano d'Accio, 64100 Teramo, Italy