Hypertension has emerged as a comorbidity in some COVID-19 patients, sparking the speculation that it is a risk factor for COVID-19. This is further complicated by several reports questioning the suitability of Angiotensin Converting Enzyme (ACE) inhibitors/angiotensin receptor blockers in COVID-19 patients since ACE2 acts as a receptor for the causative agent, the SARS-CoV-2 virus. The aim of this article is to provide a bird’s eye view on combating hypertension during the COVID-19 pandemic.
Is hypertension a risk factor for COVID-19?
Initial studies reported the occurrence of several other illnesses in patients with COVID-19 including hypertension, diabetes mellitus and kidney disease. A higher proportion of COVID-19 patients with severe disease (~24%) were found to be hypertensive compared to non-severe patients (~13%). Consistently, a recent study in ~2800 COVID-19 patients reported that patients with hypertension had a two-fold increased risk of mortality and a higher tendency to develop more severe COVID-19 disease, compared to the non-hypertensive cohort, even after taking into account confounding factors such as age. Thus, patients with elevated blood pressure are at a higher risk of developing further complications from COVID-19.
How does SARS-CoV-2 enter human cells?
A virus cannot survive on its own. It needs host cells to propagate. A selectively-leaky wall (cell membrane) surrounds the host cell, secured by gates called “receptors”. These interact only with compatible molecules, just like a lock and key. Human cells have a receptor called ACE2 and this is the gate that the novel coronavirus uses to enter inside the cell. The “key” is the Spike (S) protein which covers the entire virus surface like a crown (Fig. 1).
The ACE2 receptor is widely expressed in a variety of tissues including the intestine, heart, lungs, kidneys and blood vessels. Pneumonia is the most common clinical observation in COVID-19 patients. This could be due to the fact that the respiratory tract is the most accessible approach for transmission. The expression of ACE2 in other tissues explains the reason for comorbidities in severe conditions of this disease.
What is the role of ACE2 in blood pressure (BP) regulation?
The renin-angiotensin system (RAS) is a key regulator of blood pressure homeostasis (Fig. 2). Renin cleaves angiotensinogen to liberate Ang I, which is converted to Ang II by ACE. Ang II acts via Ang II type 1 receptor (AT1R) leading to constriction of blood vessels, resulting in elevated blood pressure. ACE2 cleaves Ang II to give rise to the peptide Ang 1-7, which interacts with the Mas receptor and lowers blood pressure by dilating blood vessels. Inhibitors of ACE (ACEIs) or AT1R blockers (ARBs) are commonly prescribed for hypertension, heart attack, heart failure and chronic kidney disease conditions.
The controversy around BP-lowering drugs in COVID-19 patients
Systematic animal studies showed conflicting data on the effect of anti-hypertensive drugs on ACE2 expression. In some rat models, higher levels/activity of ACE2 protein were observed in heart and kidney tissues with the use of ACEI Lisinopril. On the other hand, Ramipril, another ACEI, did not increase ACE2 expression in rat heart tissues. ARBs also showed contrasting effects on ACE2 expression. Since SARS-CoV-2 enters via ACE2, these animal studies raised two opposing theories on the use of ACEIs.
Theory 1: ACEIs should not be given to hypertensive COVID-19 patients
Since ACEIs are known to increase the expression of ACE2, these drugs will provide more gateways for the virus to enter the cell and flourish, thereby worsening the condition (Fig. 3).
Theory 2: ACEIs may be protective in nature for hypertensive COVID-19 patients
ARBs and ACEIs reduce Ang II-mediated hypertensive effects, thereby favouring the conversion to Ang1-7, which is anti-inflammatory and has a protective role (Fig. 4).
Human population studies suggest continuation of ACEIs/ARBs in COVID-19 patients
Human studies from Italy, UK and USA concluded that ACEIs and ARBs did not show any significant association with the severity of COVID-19. The Italy report also mentioned that ACEIs and ARBs were the most frequently used anti-hypertensive drugs. Cohort studies from China recently reported that the mortality rate of cases without anti-hypertensive treatment was significantly higher than those taking anti-hypertensive treatment.
There is no compelling clinical or scientific evidence that demonstrates the adverse or beneficial effects of ACEIs or ARBs in COVID-19 patients.
ACEIs and/or ARBs should be continued in COVID-19 patients who have already been prescribed these medications.
The clinicians should consider every individual patient’s needs before altering their ACEI/ARB treatment regimens.
In conclusion, experts recommend that the usage of ACEIs/ARBs should be continued until future studies suggest otherwise. Additional comprehensive research in this area is required to facilitate development of optimal therapeutic strategies for COVID-19 patients with comorbidities such as hypertension.
Nitish Mahapatra is a Professor in the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras. Dhanya R and Janani V are his PhD students.