key: cord-1017633-5smhgfbg authors: Ekiz, Timur; Kara, Murat; Özcan, Fırat; Ricci, Vincenzo; Özçakar, Levent title: Sarcopenia and COVID-19: A Manifold Insight on Hypertension and the Renin Angiotensin System date: 2020-07-09 journal: Am J Phys Med Rehabil DOI: 10.1097/phm.0000000000001528 sha: 7bb3eecc74d347d7530a937ba0b7d9c0a042fcb3 doc_id: 1017633 cord_uid: 5smhgfbg nan The renin-angiotensin system (RAS) is composed of widely interconnected biochemical systems ( Figure 1 ). 1 It plays an important role in the regulation of blood pressure, muscle blood flow, and skeletal muscle metabolism. Specifically, it is known that increased RAS activity plays an important role in the etiopathogenesis of age-related disorders such as hypertension, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease, and cancers -in which muscle atrophy and decline of muscle strength, endurance, and physical performance (i.e. sarcopenia) can also commonly be seen. 1, 2 Angiotensin converting enzyme (ACE) inhibitors (ACEIs) and angiotensin II type 1 (AT1) receptor blockers (ARBs) are commonly used as antihypertensive drugs via inhibiting the classical RAS pathway. The former inhibits ACE, which converts Ang I to Ang II, and the latter blocks the AT1 receptor. Both are equally important regarding blood pressure. 5 The use of ACEIs reduces the RAS activity from an earlier step than ARBs; and although ACEIs and ARBs theoretically act through the RAS, they have fundamentally different mechanisms (Table 1 ). 2, 3 The associations of ACEIs/ARBs and coronavirus disease 2019 (COVID-19) have been studied since ACE2 is the entry receptor of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). 4, 5 From this point of view, concerns regarding the use of RAS blockers during the COVID-19 pandemic have been reported. It has been put forward that hypertensive patients using ACEIs or ARBs may be at increased risk for COVID-19 mortality. 5 However, discussions regarding the use of ACEIs/ARBs for hypertension and their effects on morbidity or mortality in COVID-19 are still inconclusive. 6 Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Accordingly, we would like to provide insight into the interplay among RAS activity-related hypertension, sarcopenia, and COVID-19. First, we would like to describe the role of medications targeted to the classical RAS pathway on COVID-19, and to describe the RAS overactivity and how it affects blood pressure and sarcopenia. We believe that this is noteworthy because hypertension is a significant comorbidity among rehabilitation patients many of whom are elderly with comorbid diseases related to RAS activation. 1 Second, we would like to call attention to the overlooked and beneficial effects of RAS blockers (especially ACEIs) on muscle mass and function. We aim to create awareness among physiatrists (who need to diagnose/treat sarcopenia patients) regarding the deleterious effects of RAS overactivity, as well as the favorable effects of What is the goal of the article that we wish to review? We wish to review the recently published article by Zhang et al. 4 The authors studied the association between in-hospital use of ACEIs or ARBs and all-cause mortality in hypertensive COVID-19 patients. The authors retrospectively enrolled 1128 hypertensive adult patients diagnosed with COVID-19 in their multi-center study; 188 were taking ACEI/ARB and 940 were not. They compared all-cause mortality of COVID-19 who were taking ACEI/ARB to those who were not. The risk of 28-day all-cause mortality was lower in the ACEI/ARB group than the non-ACEI/ARB group (3.7% [7/188] vs. 9.8% [92/940]; p=0.01). After adjusting for (age, gender, comorbidities, and in-hospital medications), the mortality relationship held true (HR, 0.42; 95% Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CI, 0.19-0.92; p=0.03). The authors concluded that their inpatient use of ACEI/ARB was associated with a lower risk of all-cause mortality when compared with that of non-users. This article will be helpful for the management of hypertension during the COVID-19. However, although mentioned by the authors, enrolling 383 patients (34%) with hypertension who did not receive antihypertensive drugs into the non-ACEI/ARB group may contribute to bias. Moreover, they mentioned that the sample size was modest and did not have the power to detect if there was a differential effect between ACEI and ARB. There were a total of 99 deaths i.e. 7 out of 188 patients (3.7%) from the ACEI/ARB group and 92 out of 940 patients (9.8%) from non-ACEI/ARB. To improve upon this study, death rates among 4 groups (ACEI users, ARB users, other antihypertensive drug users, and nondrug users) could be compared. Although the protective role of antihypertensive drugs including ACEI/ARB against COVID-19 has been shown; elucidating the separate mortality rates of ACEI and ARB users, against other antihypertensive drug users and those who are not using any antihypertensive drugs would have been more instructive. Therefore, the main limitation is the lack of comparison between hypertension patients who had been treated with ACEIs and those who had been treated with ARBs. In this sense, we believe that evaluating further analyses on the individual mortality rates of different antihypertensive drugs against no drug in hypertensive patients with COVID-19 would be noteworthy. Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Concerning the interplay among ongoing COVID-19 pandemic, hypertension, ACEIs/ARBs, and ACE2 activity (the entry receptor of SARS-CoV-2); it was initially believed that ACEIs/ARBs were associated with increased risk of COVID-19, but this has been disproven. There have been only select preclinical studies about increased ACE2 expression and safety in patients with CoVID-19 7 and it is important to clarify the clinical effects of ACEIs and ARBs on COVID-19. As such, the clinical effects still need to be deciphered by prompt comparison of ACEI vs. ARB users in this regard. In light of the available evidence, withdrawal of ACEIs or ARBs in high-risk patients (i.e. coronary heart disease, myocardial infarction, heart failure) particularly in the elderly, can cause clinical instability and adverse health outcomes. 7 In short, the RAS inhibitors should be continued in patients with COVID-19. 7 Sarcopenia is the age-related loss of muscle mass and function as well as a significant determinant of physical frailty. 8 Sarcopenia is a major global health problem that is highly common in elderly. It has been suggested that the classical RAS pathway plays an essential role in mechanisms causing muscle wasting in chronic disease states. 9 Besides, in an experimental model, it has been shown that deletion of ACE2 resulted in an earlier appearance of sarcopenia. 10 The profibrotic/atrophic stimuli of the classical pathway of RAS are counterbalanced by the positive metabolic effects on the muscular tissue induced by the non-classical pathway (Fig. 1) . 1, 2, 10 Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. In this regard, hypertension is a "silent killer" causing significant comorbidity among elderly rehabilitation patients. A recent study investigating the prevalence of sarcopenia in the elderly by using machine learning found that (in order of importance), age, arterial hypertension, mininutritional assessment, number of chronic diseases and blood sodium level determined the sarcopenia. 11 Physiatrists need to consider advising their patients to continue RAS blockers (especially ACEIs) during the COVID-19 pandemic, 7 and they should also be aware of the RAS inhibitors" roles in sarcopenia. 12,13 The ACEIs can be protective against loss of muscle mass and physical performance. 12,13 It has been found that ACEI users had higher lower limb muscle mass than those using other antihypertensive drugs. 8 Additionally, continuous use of ACEIs have been found preventive in terms of gait speed and knee extensor muscle strength after a 3-year followup. 12, 13 In conclusion, RAS inhibitors (especially ACEIs) seem to have beneficial effects on not only reducing the blood pressure but also on preventing sarcopenia. ACEIs/ARBs have emerging evidence that they do not cause increased COVID-19 risk. However, future studies elucidating the separate mortality rates as regards ACEI vs. ARB users in COVID-19 would provide further clarity. Last but not least, similar to many other drugs used by rehabilitation patients, physiatrists should also be aware of the pros and cons of these antihypertensive drugs. This article may assist them in discussing such issues with their patients as well since these drugs do seem to have a direct impact on the neuromusculoskeletal system. Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Schematic drawing shows the classical (blue) and non-classical (yellow) pathway of the reninangiotensin system and their multiple effects on the skeletal muscle. The pro-fibrotic/atrophic stimuli of the Ang II/AT1R axis are counterbalanced by the positive metabolic effects on the muscular tissue induced by the Ang 1-7/Mas receptor (MasR) axis. Of note, the ACEIs/ARBs modulate such an intricate "biochemical tangle" at specific and multiple levels with different consequences from each other, especially as regards the neuromuscular system. Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Renin-angiotensin system: an old player with novel functions in skeletal muscle Pharmacological perspectives in sarcopenia: a potential role for renin-angiotensin system blockers? Clin Cases Miner Bone Metab Differences in the clinical effects of angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers: a critical review of the evidence Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19 Are patients with hypertension and diabetes mellitus at