Hypertension, a Moving Target in COVID-19: Current Views and Perspectives

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19-related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.

Keywords: COVID-19; angiotensin; blood pressure; hypertension; risk factors.

Figure 1.

The renin-angiotensin-system (RAS) and its regulation by RAS-blockers in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A, Schematic diagram of the RAS showing the role of ACE2 (angiotensin-converting enzyme 2) as a key element in the counter regulatory axis of the RAS (elements in green color, reviewed in the study by Arendse et al). ACE2 counteracts the negative effects of the Ang II (angiotensin II)/angiotensin type 1 receptor (AT1R) axis (red) in the cardiovascular system, the kidneys, and other organs including the lung upon injury, for example, in response to infections in the lung.^, B, Pharmacological treatment with ACE inhibitors or ARBs will modulate several components of the RAS either directly or by affecting feedback-loops, for example, strong upregulation of renin. Treatment with RAS-blockers may protect against organ injury, for example, in the lung, by inhibiting the damaging Ang II/AT1R axis and by activation of the protective axis, particularly via the ACE2/Ang 1-7/MasR axis. Available data indicate that ACE2 mRNA and importantly also ACE2 protein expression are not increased in airway cells of patients treated with ACEIs or angiotensin receptor blockers (ARBs) suggesting that these drugs do not impact on the infectivity of SARS-CoV-2. C, ACE2 is expressed in airway epithelial cells as mbACE2 (membrane-bound enzyme) in ciliated cells in the upper and lower respiratory epithelium and in type II pneumocytes in the lung.52 While studies using single-cell RNA-seq profiling suggested ACE2 mRNA expression also in secretory goblet cells of the airway, detailed expression analysis at the tissue level did not confirm the presence of neither ACE2 mRNA nor ACE protein expression in airway goblet cells. mbACE2 is cleaved (shedding) by ADAM17 (not shown) into a soluble form (sACE2) and thereby released in body fluids. After infection, SARS-CoV-2 binds through its viral spike protein to host cell mbACE2 in the respiratory system, thereby promoting viral cell entry and subsequent replication. D, The regulation of ACE2 in response to SARS-CoV-2 is still poorly understood. An upregulation of ACE2 mRNA expression in airway cells of patients infected with SARS-CoV-2 has been shown in several studies.^, The latter has been mechanistically linked to induction of ACE2 mRNA expression by INF (interferon), while the upregulation of mbACE2 by INF in airway cells of patients with COVID-19 remains to be shown. +, activation; -, inhibition; (), impaired effect; Ø, no effect. MasR indicates Mas receptor.

Figure 2.

Synopsis of the potential impact of hypertension, blood pressure, and antihypertensive drugs on the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the course of coronavirus disease (COVID-19). The overall impact of the parameters shown on the left on the risk of infection with SARS-CoV-2 and the risk of death as shown in available studies are indicated by the symbols. The impact of these parameters on the progression of COVID-19 or the development of long-term sequelae, for example, post-COVID syndrome and long-COVID is unclear and warrants future research; other first-line BP-lowering drugs include calcium channel blockers, thiazide/thiazide-like diuretics, and β-blockers. (), possible effect; Ø, no effect; ↥, increased risk; ?, unclear and/or no data available. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP indicates blood pressure; MRA, mineralocorticoid receptor antagonist; and SBP, systolic blood pressure.