Hypertension in COVID-19, A Risk Factor for Infection or A Late Consequence?

There are a lot of data about the correlation of SARS-CoV-2 infection and hypertension (HTN), but most of them are in the increased risk of morbidity and mortality in patients with HTN. SARS-CoV-2 can interfere with host cells through the renin-angiotensin system (RAS) via the angiotensin-converting enzyme 2 (ACE2) receptor. RAS activation is associated with pro-inflammatory effects through the ACE/Ang II/ Angiotensin II type 1 receptor (AT1R) pathway or anti-inflammatory effects through ACE2/Ang1-7/Mas axis. In the current paper, we discuss the pathophysiology of newly diagnosed HTN and its effect on morbidity in patients with coronavirus disease 2019 (COVID-19).

Introduction

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) firstly reported in Wuhan in 2019 (1), China, that caused more than 517 million confirmed cases and almost 6.2 million deaths until 6 May 2022 (2). It is shown that cardiovascular diseases and risk factors such as hypertension (HTN) are associated with more severe symptoms in affected individuals including dyspnea, and hypoxia. These patients need intensive care unit (ICU) that represent the increased likelihood of morbidities, and even mortality (3). On the other hand, HTN may be a consequence of COVID-19, due to the over-activity of the reninangiotensin system (RAS) (4).

During the COVID-19 pandemic disease, especially during lockdown and quarantine, diagnostic and therapeutic interventions for HTN were reduced significantly, which deteriorates the long-term consequences of HTN and cardiovascular events (5, 6). In addition, studies reported that the COVID-19 pandemics has changed the treatment strategies of HTN in order to have a better management of this condition in patients (7). In this study, we review the association between COVID-19 and HTN as a risk factor for the infection, and a consequence of the infection.

COVID-19 and RAS

SARS-CoV-2 penetrates host cells using surface spike protein through the angiotensin-converting enzyme 2 (ACE2) receptor that interferes with host cells via RAS (8). Recent studies showed that RAS over-activation might have pro-inflammatory, profibrotic, and vasoconstrictive effects by reactive oxygen species (ROS) production and cytokines release through ACE/Ang II/ Angiotensin II type 1 receptor (AT1 R) pathway (9). However, RAS can act through an alternative pathway, the ACE2/Ang1-7/Mas axis, which is a counter-regulator of classic pathway causing anti-inflammatory effects (10). It was revealed that, the ACE2/Ang1-7/Mas axis, may be downregulated in COVID-19 infection due to eliminating ACE2 expressing cells by virus. This issue may cause the over expression of ACE/Ang II/AT1 R pathway (11). Since angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists overexpressed the ACE2 receptor, it has been thought that these drugs can lessen the severity of the disease and cause ACE2/ Ang1-7/Mas axis upregulation. These properties associated with beneficial effects on lung function. Therefore, these drugs should not be withheld during COVID-19 (12).

Inflammation

SARS-CoV-2 infection can induce cytokine storm via different mechanisms. The activation of Ang II, which promotes production of pro-inflammatory cytokines such as IL-6 and TNF-alpha causing an influx of inflammatory cells to the infected sites results in vascular injury, fibrosis and even thrombosis (13). In addition, SARS-CoV-2 infection can induce production of ROS, which stimulates the synthesis of NF-κB (14). This usually results in increment of cytokines and the cytokine storm (15). On the other hand, the role of inflammation in HTN has been investigated. It seems that systemic inflammation may cause arterial stiffness associated with elevating blood pressure until the rage of HTN (16). In fact, oxidative stress alongside chronic inflammation causes changing the arterial walls, increase in intima-media thickness, and endothelial dysfunction (17).

It was shown that endothelial dysfunction may be associated with essential HTN (18) and severe endothelial injury in the severe COVID-19 (19). It seems that endothelial dysfunction resulted from HTN, may exacerbate COVID-19 symptoms in patients with HTN; also, and in some patients without HTN, endothelial dysfunction resulted from COVID-19 infection may develop HTN in near future.

Hypertension: a risk factor for COVID19 or its consequence?

The endothelial dysfunction caused by HTN may influence the outcome of COVID-19. In the evaluation of newly onset HTN in COVID-19, there are many of studies that supported this concept. In a study in late 2021 on 211 COVID-19 patients, new onset HTN was seen in 18 patients during a 30-day followup (20). In another study by Chen et al. (4) on 366 patients, new onset HTN was observed in 190 patients without history of HTN, with high levels of Ang II and cardiac troponin. In addition, Bekbossynova et al. (21) observed a case of COVID-19 that was manifested as sudden HTN. However, conflicting results observed in a cohort study in China on more than 1,700 COVID-19 patients with a six months follow-up, without reports of newly diagnosed HTN (7).

According to our explorations, there is a close relationship between HTN and COVID-19 infection. Each of them can induce and exacerbate the other one; although, more studies are needed to investigate new onset HTN after COVID-19.

How should we battle?

It was suggested that the mortality rate is similar in adjusted model analysis, in the context of beta blocker, ACEIs or ARBs consumption in COVID-19 patients (22). Furthermore, large scale studies reduced the uncertainties in the context of medication controversies in COVID-19 patients with HTN; however, further cohort studies are needed to confirm this hypothesis.

Conclusion

According to our explorations, there is a close association between HTN and COVID-19 infection. Each of them can induce and exacerbate the other one; although, to have a better insight, more studies are needed to investigate new onset HTN after COVID-19.