key: cord-316186-254z62e4
authors: Kario, Kazuomi; Morisawa, Yuji; Sukonthasarn, Apichard; Turana, Yuda; Chia, Yook‐Chin; Park, Sungha; Wang, Tzung‐Dau; Chen, Chen‐Huan; Tay, Jam Chin; Li, Yan; Wang, Ji‐Guang
title: COVID‐19 and hypertension—evidence and practical management: Guidance from the HOPE Asia Network
date: 2020-07-09
journal: J Clin Hypertens (Greenwich)
DOI: 10.1111/jch.13917
sha: 
doc_id: 316186
cord_uid: 254z62e4

There are several risk factors for worse outcomes in patients with coronavirus 2019 disease (COVID‐19). Patients with hypertension appear to have a poor prognosis, but there is no direct evidence that hypertension increases the risk of new infection or adverse outcomes independent of age and other risk factors. There is also concern about use of renin‐angiotensin system (RAS) inhibitors due to a key role of angiotensin‐converting enzyme 2 receptors in the entry of the SARS‐CoV‐2 virus into cells. However, there is little evidence that use of RAS inhibitors increases the risk of SARS‐CoV‐2 virus infection or worsens the course of COVID‐19. Therefore, antihypertensive therapy with these agents should be continued. In addition to acute respiratory distress syndrome, patients with severe COVID‐19 can develop myocardial injury and cytokine storm, resulting in heart failure, arteriovenous thrombosis, and kidney injury. Troponin, N‐terminal pro‐B‐type natriuretic peptide, D‐dimer, and serum creatinine are biomarkers for these complications and can be used to monitor patients with COVID‐19 and for risk stratification. Other factors that need to be incorporated into patient management strategies during the pandemic include regular exercise to maintain good health status and monitoring of psychological well‐being. For the ongoing management of patients with hypertension, telemedicine‐based home blood pressure monitoring strategies can facilitate maintenance of good blood pressure control while social distancing is maintained. Overall, multidisciplinary management of COVID‐19 based on a rapidly growing body of evidence will help ensure the best possible outcomes for patients, including those with risk factors such as hypertension.

The infectious disease caused by the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), COVID-19, broke out in Wuhan, China, and spread to almost every country in the world. Millions of people have been infected, many have died, and everyday life has changed completely. The disease is accompanied by range of different symptoms ( Figure 1 ). Rapidly accumulating data show that prognosis for patients with COVID-19 is good in those with mild disease, but severe cases show relatively asymptomatic early progression followed by rapid worsening after symptom onset, culminating in acute respiratory distress syndrome (ARDS) and significant disease manifestations ( Figure 2 ). The presence of SARS-CoV-2 has been detected in multiple organs on autopsy, including the pharynx, lungs, heart, liver, brain and kidneys, highlighting the multiorgan tropism of this virus. 1 Early clinical experience suggested that older age and the presence of a number of comorbidities, including hypertension, cardiovascular disease, diabetes mellitus and chronic respiratory disease increased the risk of death in patients with 3 In addition, the renin-angiotensin aldosterone (RAS) system (specifically the angiotensin-converting enzyme 2 [ACE2] protein) has been identified as playing an important role in facilitating entry of coronaviruses, including SARS-CoV-2, into target cells, especially in the lungs. 4, 5 Therefore, it has been suggested that angiotensin receptor blockers (ARBs) and ACE inhibitors, which affect ACE2 expression, may influence the susceptibility to and severity of infection with SARS-CoV-2. [6] [7] [8] [9] [10] [11] Hypertension is very common, affecting an estimated 1.39 billion individuals worldwide, 12 and the prevalence of hypertension increases with age (affecting approximately 70% of older adults). 13 In addition, RAS inhibitors such as ACE inhibitors and ARBs are recommended and widely used for the treatment of hypertension. [14] [15] [16] However, hypertension is not a single clinical entity, but it instead manifests as a number of different phenotypes. In Asians, the disease is characterized by salt sensitivity, high rates of masked hypertension, exaggerated morning BP surge, and nocturnal hypertension. 17 Nearly half of all patients with hypertension worldwide (44%) live in south or east Asia. 18 The HOPE Asia Network was established in 2016 and is a member of the World Hypertension League. 19, 20 The mission of the HOPE Asia Network is to improve the management of hypertension and organ protection toward achieving "zero" cardiovascular events in Asia. 19, 20 This has become even more relevant in the current pandemic, with high rates of infection in several Asian countries.

This guidance from the HOPE Asia Network summarizes the latest findings on COVID-19 and hypertension, including evidence-based recommendations for the management of hypertension during the current pandemic.

On March 20, 2020, the Italian Institute of Health announced that there had been 3200 COVID-19 deaths in Italy. 21 The patients who died had an average age of 78.5 years (median 80 years, range 31-103 years) and 98.7% had at least one comorbidity. 21 Hypertension was a common comorbidity in Italian cases, affecting 73.8% of patients, 52% of whom were taking ARBs or ACE inhibitors. 21 However, home blood pressure monitoring strategies can facilitate maintenance of good blood pressure control while social distancing is maintained. Overall, multidisciplinary management of COVID-19 based on a rapidly growing body of evidence will help ensure the best possible outcomes for patients, including those with risk factors such as hypertension.

F I G U R E 1 Wide range of symptoms in patients with COVID-19 (reproduced, with permission, from Clerkin KJ et al, 2020) 22 there are number of factors that could potentially confound a possible relationship between hypertension and severe COVID-19 (Table 1) . [22] [23] [24] [25] [26] [27] The first is age: both severe COVID-19 and hypertension are common in the elderly. In addition, the identified risk factors (Table 1) are generally associated with aging and/or vascular disorders, both of which are common in patients with hypertension. Therefore, the risk of developing severe COVID-19 is more likely to be due to underlying vascular endothelial dysfunction and/or organ damage than high blood pressure (BP) per se. ACE2 receptors are expressed by endothelial cells, 28 and post-mortem examinations have detected the presence of viral infection in endothelial cells. 29 

The spike protein on the surface of SARS-CoV-2 binds to the extracellular domain of transmembrane ACE2, with S protein priming by transmembrane serine protease 2 (TMPRSS2), to gain entry to host F I G U R E 2 Variety of organ damage seen in patients with COVID-19. ARDS, acute respiratory distress syndrome

Pre-existing hypertension appears to be common in pa- Interaction of Ang II with angiotensin type 1 receptors (AT1R) activates A Disintegrin And Metalloproteinase 17 (ADAM17) on the cell membrane via phosphorylation. 40 In turn, ADAM17 cleaves the precursors of tumor necrosis factor-α (TNFα) and interleukin (IL)-6 receptor-α (IL-6Rα) in the cell membrane to release TNFα and soluble IL-6Rα. 41 TNFα activates the nuclear transcription factor system NF-κB to induce the production of various inflammatory cytokines, including IL-6 ( Figure 4) . 42 This represents a potential mechanism for the cytokine storm seen in some patients with COVID-19 and highlights the potential for agents blocking cytokine pathways (especially the IL-6-STAT3 axis) in managing COVID-19-related cytokine storm. 43 The fact that the SARS-CoV-2 virus uses ACE2 as a mechanism to enter and infect cells meant that there was concern that cells with high ACE2 expression would be most susceptible to infection with SARS-CoV-2. Given that ARB and ACE inhibitors have been shown experimentally to increase expression of ACE2 on cell membranes, 28, 44 there was much discussion about the potential for higher infection rates and more severe disease in patients being treated with these agents.

Despite the theoretical possibility that use of RAS inhibitors increases the risk of infection with SARS-CoV-2 and the severity of COVID-19 illness, analyses including patients from the current pandemic indicate that this does not seem to be the case ( Table 2 ).

ARBs has been evaluated in at least three published studies to date ( Data from four studies published by early May 2020 also failed to find a significant association between RAS inhibitor use and worse outcomes in patients with COVID-19 (Table 2) . [48] [49] [50] In one retrospective case series, the proportion of patients using ACE inhibitors or ARBs did not differ significantly between those with severe vs non-severe COVID-19, or between survivors and non-survivors. 48 However, the in-hospital COVID-19 mortality rate was higher in patients with vs without hypertension (21% vs 11%). 48 In the other studies, death rates for patients taking ACE inhibitors and/or ARBs were actually lower than those in patients not receiving these antihypertensive therapies. 49, 50 One of the studies from China reported that levels of the inflammatory markers high sensitivity C-reactive protein and procalcitonin were significantly lower in patients with hypertension who were vs were not receiving ACE inhibitors or ARBs. 49 F I G U R E 3 SARS-CoV-2 and the reninangiotensin system. ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker

High levels of a number of biomarkers are indicative of severe COVID-19 ( Table 3) 

There are two possible mechanisms of cardiovascular damage in COVID-19. The first is direct viral infection of myocardial and vascular cells, and the other is a systemic inflammatory reaction (or cytokine storm) ( Figure 5 ). Myocardial injury at the time of admission or due to disease progression is a strong indicator of poor prognosis in patients with COVID-19. Troponin is a highly sensitive and wellknown marker of myocardial injury.

A systematic review and meta-analysis of data published between 

D-dimer is a biomarker that reflects activation of coagulation and fibrinolysis. 54 

Key points regarding the clinical management of COVID-19, particularly in patients with hypertension, based on evidence published before May 5, 2020, are shown in Table 4 .

Data that have been rapidly compiled during the pandemic to Lockdown requirements could impact on the ability of individuals to get regular exercise. Regular exercise is important for maintaining health status 61 and to counteract the negative consequences of cardiovascular, metabolic, and respiratory diseases. 62 Even if unable to get outside, continuing some form of home-based exercise would be beneficial, especially in older adults. 63 Maintaining regular exercise could help to ensure that the current viral pandemic does not contribute to the worldwide obesity epidemic, which in turn increases the rate of cardiovascular and metabolic comorbidities. 64 Ensuring that the world population is not burdened by high rates of noncommunicable diseases might help lessen the impact of future pandemics given that patients with comorbidities tend to fare poorly during an infectious disease pandemic. 64 Another potential benefit of physical activity is its ability to stimulate immune function, 65 something that is highly relevant during a global pandemic.

Health care professionals should also be aware of the potential non-infectious impacts of COVID-19. For example, non-infected individuals might be at risk of developing stress-related physical health conditions (such as gastrointestinal disturbances and cardiovascular disease) and psychological disturbances (such as anxiety and depression).

Strict lockdown and social distancing rules are being enforced in many countries to slow the spread of the novel coronavirus. In addition, a large proportion of "elective" or "non-essential" procedures have been postponed or canceled to allow health care systems to cope with the influx of infectious disease cases. This has created a requirement for a large proportion of health consultations to be conducted remotely. Telemedicine strategies are ideally suited to facilitating patient management in the absence of face-to-face consultations, and the value of this approach (which has otherwise been slow to be widely used in clinical practice) has become clear. 66, 67 One of the hidden "blessings" of the COVID-19 pandemic may be the widespread adoption of telemedicine approaches to improve patient management.

Out-of-office BP monitoring is a recommended approach for the diagnosis and management of hypertension. [14] [15] [16] [68] [69] [70] [71] [72] [73] [74] [75] Therefore, this field of medicine is better placed than many to be able to continue to effectively manage patients during a global pandemic. 

Patients with hypertension are at increased risk of morbidity and mortality if they become infected with SARS-CoV-2, although this is confounded by other factors such as age and vascular disorders.

However, all usual antihypertensive therapy including RAS inhibitors should continue. Physicians need to take a holistic approach to patient management due the wide range of possible complications, and biomarkers can provide important prognostic information. Overall, multidisciplinary management of COVID-19 based on a rapidly growing body of evidence will help ensure the best possible outcomes for patients, including those with risk factors such as hypertension.

We would like to express our gratitude to Ayako Okura, the academic editorial coordinator of the Department of Cardiology, Jichi

Medical School, and Yukiko Suzuki, the academic coordinator, for their assistance with data gathering and figure preparation. Medical writing assistance was provided by Nicola Ryan, independent medical writer, funded by Jichi Medical University.

All authors report no potential conflicts of interest in relation to this article.

https://orcid.org/0000-0002-8251-4480

Yook-Chin Chia https://orcid.org/0000-0003-1995-0359

Jam Chin Tay https://orcid.org/0000-0001-7657-4383

Ji-Guang Wang https://orcid.org/0000-0001-8511-1524

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How to cite this article

Hypertension Cardiovascular Outcome Prevention, Evidence in Asia (HOPE Asia) Network. COVID-19 and hypertension-evidence and practical management: Guidance from the HOPE Asia Network